Indol-2-one derivatives

ABSTRACT

A compound of formula II&#39; ##STR1## in which 
     R I  is an ethoxy group or a chlorine atom; 
     R II  is hydrogen, a chlorine atom or a methyl group; 
     R III  is a chlorophenyl group or a methoxyphenyl group; 
     R IV  is an amino group, a group NR 9  R 10  or NR 9  R XI , or a piperazin-1-yl radical substituted in the 4-position by a (C 2  -C 10 )alkylene group substituted by an amino group which is free or carries a protective group; 
     R 10  is (CH 2 ) p  R 35  or a (C 2  -C 10 )alkylene group substituted by R 21  ; 
     R XI  is a (C 1  -C 12 )alkyl group or a group ω-R 32  R 33  N(C 1  -C 4 )-alkylcarbonyl; and 
     R 21  is R 36  ; a group OR 37  ; a group NR 32  R 33  ; a cyano group; a group S(C 1  -C 7 )alkyl; a group SO(C 1  -C 7 )alkyl; or a group SO 2  (C 1  -C 7 )alkyl; 
     R 35  is a piperid-4-yl group which is unsubstituted or substituted in the 1-position by a (C 1  -C 7 )alkoxycarbonyl group or by a (C 1  -C 7 )alkyl group; or a pyrid-2-yl group; 
     R 37  is R 13  ; a (C 3  -C 7 )cycloalkyl group; a (C 1  -C 6 )alkylene group substituted by R 24  ; a (C 2  -C 6 )alkylene group substituted by a hydroxyl or a (C 1  -C 7 )alkoxy group; or a (C 2  -C 6 )alkylene group substituted by an amino group which is free or substituted by one or two (C 1  -C 7 )alkyl groups or by a protective group; 
     R 24  is a carboxyl group; a (C 1  -C 7 )alkoxycarbonyl group; a benzyloxycarbonyl group; or a carbamoyl group which is free or substituted by one or two (C 1  -C 7 )alkyl groups.

This application is a Division of application Ser. No. 08/500,924, filedJul. 31, 1995, now U.S. Pat. No. 5,594,023 which is a 371 ofPCT/FR94/01528 filed Dec. 23, 1996.

The present invention relates to 1,3-dihydroindol-2-one derivativessubstituted in the 3-position by a nitrogen-containing group, to theirpreparation and to the pharmaceutical compositions in which they arepresent.

The compounds according to the present invention have an affinity forthe vasopressin and/or ocytocin receptors.

Vasopressin is a hormone known for its antidiuretic effect and itseffect in the regulation of arterial pressure. It stimulates severaltypes of receptors, namely V₁ (V_(1a), V_(1b)) and V₂. These receptorsare localized in the liver, vessels (coronary, renal, cerebral),platelets, kidney, uterus, adrenal glands, central nervous system andpituitary gland. Ocytocin has a peptide structure similar to that ofvasopressin. The ocytocin receptors are also found on the smooth muscleof the uterus, as well as on myoepithelial cells of the mammary gland,in the central nervous system and in the kidney. The localization of thedifferent receptors is described in: S. JARS et al., Vasopressin andoxytocin receptors: an overview, in Progress in Endocrinology, H. IMURAand K. SHIZURNE ed., Experta Medica, Amsterdam, 1988, 1183-1188, and inthe following articles: Presse Medicale, 1987, 16 (10), 481-485; J. Lab.Clin. Med., 1989, 114 (6), 617-632; and Pharmacol. Rev., 1991, 43 (1),73-108. Vasopressin thus exerts cardiovascular, hepatic, antidiureticand aggregating effects and effects on the central and peripheralnervous system and in the uterine domain. ocytocin is involved inparturition, lactation and sexual behavior.

The compounds according to the present invention make it possibleselectively either to mimic the effects of the hormone (in the case ofagonists) or to inhibit them (in the case of antagonists). Vasopressinreceptor antagonists can affect the regulation of the central andperipheral circulation, especially the coronary, renal and gastriccirculation, as well as the regulation of hydration and the release ofadrenocorticotrophic hormone (ACTH). Vasopressin agonists canadvantageously replace vasopressin or its analogs in the treatment ofdiabetes insipidus; they can also be used in the treatment of enuresisand in the regulation of hemostasis: treatment of hemophilia and vonWillebrand's syndrome, antidote to platelet aggregating agents, F. A.LASZLO, Pharmacol. Rev., 1991, 43, 73-108; and Drug Investigation, 1990,2 (Suppl. 5), 1-47. The hormones themselves, namely vasopressin andocytocin, and some of their peptide or non-peptide analogs are used intherapeutics and have been found to be effective. Several reviews andnumerous literature articles may be mentioned: Vasopressin, P. GROSS etal. ed., John Libbey Eurotext, 1993, in particular 243-257 and 549-562;F. A. LASZLO and F. A. LASZLO Jr., Clinical perspectives for vasopressinantagonists, Drug News Perspect., 1993, 6 (8); W. G. NORTH, J. Clin.Endocrinol., 1991, 73, 1316-1320; J. J. LEGROS et al., Prog.Neuro-Pharmacol. Biol. Psychiat., 1988, 12, 571-586; K. E. ANDERSSON etal., Drugs Today, 1988, 24 (7), 509-528; D. L. STUMP et al., Drugs,1990, 39, 38-53; S. CALTABIANO et al., Drugs Future, 1988, 13, 25-30; Y.MURA et al., Clin. Nephrol., 1993, 40, 60-61; and Faseb J., 1994, 8 (5),A 587, 3398.

Thus the compounds according to the invention are useful especially inthe treatment of complaints of the central and peripheral nervoussystem, the cardiovascular system, the renal domain and the gastricdomain and in disorders of sexual behavior, in man and animals.

Patent ZA 83 09532 describes in particular a 1,3-dihydroindol-2-onederivative of the formula ##STR2##

This compound is useful as a converting enzyme inhibitor and as anantihypertensive.

Patent application GB 1 125 671 describes 3-amino-3-arylindolonederivatives of the formula ##STR3## in which:

R is hydrogen or a C₁ -C₄ -alkyl or C₁ -C₄ -dialkylamino group;

A is a C₂ -C₅ -alkylene;

R"₁ and R"₂ are each an alkyl or, together with the nitrogen atom towhich they are bonded, are a heterocyclic radical, for example thepiperidino, pyrrolidino or morpholino radical;

R"₃ and R"₄ are each hydrogen, a C₁ -C₄ -alkyl, a C₁ -C₄ -alkoxy or ahalogen; and

Ar is an optionally substituted benzyl or phenyl.

These compounds are useful as diuretics.

Several patent applications have recently described families ofcompounds of non-peptide structure which are active on the vasopressinand/or ocytocin receptors. There may be mentioned patent applications EP382 185, EP 444 945, EP 514 667, EP 469 984 and EP 526 348, patentapplications WO 91/05549 and WO 93/15051 and, more particularly, patentapplication JP-03/127732. This last patent application describesindole-3-propionic acid derivatives of the formula ##STR4## in which:

R""₁ is hydrogen, an alkyl, an alkenyl, a phenylalkyl, atetrahydrofuryl, an alkoxycarbonyl, an alkoxycarbonylalkyl, acarboxyalkyl or an alkanoyl;

R""₂ is hydrogen, a hydroxyl, an alkoxy, an alkyl, a phenylalkyl, aphenylalkoxy or a halogen;

R""₃ is a hydrogen, an alkoxy, a free or substituted amino group or anamino acid residue;

R""₄ is hydrogen, an alkyl or a phenylalkyl; and

R""₅ is a benzoyl, a phenyl, an alkyl, a phenylalkenylcarbonyl, athienylcarbonyl, a phenylsulfonyl, a pyridylcarbonyl or animidazolylcarbonyl, it being possible for the phenyl and alkyl groups ofthe substituent R""₅ to be substituted.

These compounds are vasopressin antagonists.

U.S. Pat. No. 4 803 217 claims hapalindolinones obtained by fermentationwhich are vasopressin antagonists. These compounds have the followingformula: ##STR5## in which R is H or Cl.

According to one of its features, the present invention relates tocompounds of the formula ##STR6## in which:

R₁ and R₂ are each independently a hydrogen; a halogen; a (C₁ -C₇)alkyl;a (C₁ -C₇)alkoxy; or a trifluoromethyl;

R₃ is a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl; a cyclohexyl substituted byone or two (C₁ -C₄)alkyls; a cyclohexylmethyl; a phenyl which isunsubstituted or monosubstituted or polysubstituted by a halogen, a (C₁-C₇)-alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy or an acetoxy; ora benzyl which is unsubstituted or monosubstituted or polysubstituted bya halogen, a (C₁ --C₇)-alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxyor an acetoxy;

R₄ is an azido; a 2,2-dimethylhydrazino group; a (C₁-C₇)alkylsulfonamido; a phenylsulfonamido in which the phenyl isunsubstituted or monosubstituted or polysubstituted by a halogen, a (C₁-C₇)alkyl, a hydroxyl, a (C₁ -C₇ )alkoxy, a benzyloxy or an acetoxy; adimethylaminosulfonamido; a group NR₇ R₈ ; a group NR₉ R₁₀ ; a group NR₉R₁₁ ; a heterocyclic radical R₁₂ ; a piperazin-1-yl substituted in the4-position by a (C₂ -C₁₀)alkylene group substituted by an amino groupwhich is free or carries a protective group; a lactoylamino group; amandeloylamino group; an N'-(1-phenylethyl)ureido group; or an N'-(1-naphth-1-ylethyl)ureido group;

R₅ is hydrogen or has one of the meanings given for R₆ ;

R₆ is a halogen; a (C₁ -C₇)alkyl; a trifluoromethyl; a cyano; anaminomethyl in which the amino is free or substituted by one or two (C₁-C₇)alkyls; a nitro; a group NR₉ R₁₁ ; a heterocyclic radical selectedfrom pyrrol-1-yl, Δ3-pyrrolin-1-yl, pyrrolidin-1-yl and morpholin-4-yl;a group OR₁₃ ; a group SR₁₃ ; a guanidino which is unsubstituted orsubstituted in the 3-position by one or two (C₁ -C₇)alkyls, a phenyl ora benzyl; a formyl; a (C₁ -C₇)alkylcarbonyl; a carbamoyl substituted byR₁₄ and R₁₅ ; a thiocarbamoyl which is free or substituted by one or two(C₁ -C₇)alkyls; a sulfamoyl substituted by R₁₆ and R₁₇ ; a carboxyl; a(C₁ -C₇)alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a (C₁-C₇)alkylsulfonamido; a phenylsulfonamido in which the phenyl isunsubstituted or monosubstituted or polysubstituted by a halogen, a (C₁-C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy or an acetoxy; adimethylaminosulfonamido; or a 2-(4-methylphenyl)benzamido;

or R₅ and R₆, together with the phenyl to which they are bonded, form agroup ##STR7## with the proviso that X is --SO₂ --; R₇ is a (C₁-C₇)alkoxycarbonyl;

R₈ is a (C₁ -C₇)alkoxycarbonylamino; or an N-methyl-N-(C₁-C₇)alkoxycarbonylamino;

R₉ is a hydrogen; or a (C₁ -C₇)alkyl;

R₁₀ is a group CR₁₈ R₁₉ R₂₀ ; a group (CH₂)_(p) R₃₅ ; a (C₂-C₁₀)alkylene substituted by R₂₁ ; a group CH₂ CN; a group C(CH₃)(CH₂OH)₂ or C(CH₂ OH)₃ ; a non-aromatic C₃ -C ₁₅ carbocyclic radical; aphenyl which is unsubstituted or monosubstituted or polysubstituted by ahalogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy, anacetoxy, a nitro or an amino which is free or substituted by one or two(C₁ -C₇)alkyls; a benzyl in which the phenyl is unsubstituted ormonosubstituted or polysubstituted by a halogen, a (C₁ -C7)alkyl, ahydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy, an acetoxy, a nitro or an aminowhich is free or substituted by one or two (C₁ -C₇)alkyls; a phenethylin which the phenyl is unsubstituted or monosubstituted orpolysubstituted by a halogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy, an acetoxy, a nitro or an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls; or a phenethyl in which thephenyl is substituted by a 3,4-methylenedioxy or a 3,4-ethylenedioxy;

R₁₁ is a hydrogen; a (C₁ -C₁₂)alkyl; a (C₃ -C₇)cycloalkylmethyl; a groupOR₁₃ ; a formyl; a (C₁ -C₇)alkylcarbonyl; a (C₁ -C₇)alkylthiocarbonyl; a(C₃ -C₇)cycloalkylcarbonyl; a (C₃ -C₇)cycloalkylthiocarbonyl; a benzoylwhich is unsubstituted or monosubstituted or polysubstituted by ahalogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy oran acetoxy; a phenylacetyl in which the benzene ring is unsubstituted ormonosubstituted or polysubstituted by a halogen, a (C₁ -C₇)alkyl, ahydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy or an acetoxy; apyridylcarbonyl; a thienylcarbonyl; a furylcarbonyl; apiperid-4-ylcarbonyl which is unsubstituted or substituted in the1-position by a (C₁ -C₇)-alkyl or by a protective group; a (C₁-C₇)alkoxycarbonyl; a phenoxycarbonyl; a phenoxythiocarbonyl; abenzyloxycarbonyl; a carbamoyl substituted by R₂₂ and R₂₃ ; athiocarbamoyl substituted by R₂₂ and R₂₃ ; a group CH₂ R₃₆ ; an ω-R₂₄(C₁ -C₆)alkylcarbonyl; or ω-R₃₂ R₃₃ N(C₁ -C₄)alkylcarbonyl;

R₁₂ is a morpholin-4-yl; a thiomorpholin-4-yl; an azetidin-1-yl which isunsubstituted or substituted in the 2-position by a carboxyl orsubstituted in the 3-position by an amino which is free or carries aprotective group; a perhydroazepin-1-yl; a piperazin-1-yl which isunsubstituted or substituted in the 4-position by R₂₅ ; a piperid-1-ylwhich is unsubstituted or substituted by R₂₆ ; a pyrrolidin-1-yl whichis unsubstituted or substituted by R₂₇ ; or a thiazolidin-3-yl which isunsubstituted or substituted by R₂₇ ;

R₁₃ is a hydrogen; a (C₁ -C₇)alkyl; a benzyl; an allyl; or atetrahydropyran-2-yl;

R₁₄ and R₁₅ are each independently hydrogen; or a (C₁ -C₇)alkyl; R₁₅ canalso be a (C₁ -C₇)alkylene substituted by R₂₄, a cyano, atrifluoromethyl or an amino which is free or substituted by one or two(C₁ -C₇)-alkyls; a (C₃ -C₇)cycloalkyl; a phenyl which is unsubstitutedor monosubstituted or polysubstituted by a halogen, a (C₁ -C₇)alkyl, ahydroxyl, a (C₁ -C₇)alkoxy or a benzyloxy; or a group R₂₈ ;

or R₁₄ and R₁₅, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ;

R₁₆ and R₁₇ are each independently a hydrogen; or a (C₁ -C₇)alkyl; R₁₇can also be a (C₃ -C₇)cycloalkyl; or a group R₂₈ ;

or R₁₆ and R₁₇, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ;

R₁₈ is a (C₁ -C₇)alkyl; a phenyl; a benzyl; a cyclohexylmethyl; aphenethyl; an imidazol-4-ylmethyl which is free or carries a protectivegroup; an indol-3-yl-methyl which is free or carries a protective group;a hydroxymethyl which is free or carries a protective group; a2-hydroxyethyl which is free or carries a protective group; a1-hydroxyethyl which is free or carries a protective group; a4-hydroxybenzyl which is free or carries a protective group; amercaptomethyl which is free or carries a protective group; a2-mercaptoethyl which is free or carries a protective group; a2-methylthioethyl; a 2-methylsulfinylethyl; a 2-methylsulfonylethyl; a4-aminobutyl which is free or carries a protective group; a3-aminopropyl which is free or carries a protective group; acarboxymethyl which is free or carries a protective group; a2-carboxyethyl which is free or carries a protective group; acarbamoylmethyl; a 2-carbamoylethyl; a 3-guanidinopropyl which is freeor carries a protective group; or a non-aromatic C₃ -C₁₅ carbocyclicradical;

R₁₉ is hydrogen; R₁₉ can also be a (C₁ -C₇)alkyl if R₁₈ is a (C₁-C7)alkyl;

or R₁₈ and R₁₉, together with the carbon atom to which they are bonded,form a non-aromatic C₃ -C₁₅ carbocyclic radical;

R₂₀ is R₂₄ ; a group CH₂ OR₁₃ ; or an aminomethyl in which the amino isfree or substituted by one or two (C₁ -C₇)alkyls or by a protectivegroup;

R₂₁ is R₃₆ ; a group OR₃₇ ; a group NR₂₂ R₃₃ ; a cyano; a group S(C₁-C₇)alkyl; a group SO(C₁ -C₇)alkyl; or a group S₂ (C₁ -C₇)alkyl;

R₂₂ and R23 are each independently a hydrogen; or a (C₁ -C₇)alkyl; R₂₃can also be a (C₃ -C₇)cycloalkyl; a group CR₁₈ R₁₉ R₂₀ ; a group CH₂ R₂₄; a group C(CH₃)--(CH₂ OH)₂ or C(CH₂ OH)₃ ; or a (C₂ -C₆)alkylenesubstituted by R₂₉ ;

or R₂₂ and R₂₃, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ; or acis-2,6-dimethylpiperid-1-yl;

R₂₄ is a carboxyl; a (C₁ -C₇)alkoxycarbonyl; a benzyloxycarbonyl; or acarbamoyl which is free or substituted by one or two (C₁ -C₇)alkyls;

R₂₅ is a (C₁ -C₇)alkyl; a phenyl; a benzyl; a formyl; a (C₁-C₇)alkylcarbonyl; a (C₁ -C₇)alkoxycarbonyl; or a benzyloxycarbonyl;

R₂₆ is R₂₄ ; an amino which is free or substituted by one or two (C₁-C₇)alkyls or by a protective group; a group OR₁₃ ; or a group CH₂ OR₁₃;

R₂₇ is R₂₄ ; a group CH₂ R₂₄ ; a group CH₂ OR₁₃ ; or an aminomethyl inwhich the amino is free or substituted by one or two (C₁ -C₇)alkyls orby a protective group;

R₂₈ is a group CH(CH₂ OH)₂, CH(CH₃)CH₂ OH, C(CH₃)--(CH₂ OH)₂, C(CH₃)₂CH₂ OH, C(CH₂ OH)₃ or CH₂ CH₂ OH;

R₂₉ is a group R₂₄ ; a group OR₁₃ ; or a group NR₃₀ R₃₁ ;

R₃₀ and R₃₁ are each independently a hydrogen; or a (C₁ -C₇)alkyl;

or R₃₀ and R₃₁, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ;

R₃₂ and R₃₃ are each independently a hydrogen; or a (C₁ -C₇)alkyl; R₃₃can also be an acetyl; a phenyl; a benzyl; a (C₁ -C₇)alkoxycarbonyl; abenzyloxycarbonyl; a (C₁ -C₆)alkylene substituted by R₂₄ ; a (C₂-C₆)alkylene substituted by a hydroxyl or a (C₁ -C₇)alkoxy; or a (C₂-C₆)alkylene substituted by an amino which is free or substituted by oneor two (C₁ -C₇)alkyls or by a protective group;

or R₃₂ and R₃₃, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ;

R₃₄ is a formyl; a (C₁ -C₇)alkylcarbonyl; a (C₁ -C₇)-alkoxycarbonyl; aphenoxycarbonyl; a carbamoyl substituted by two (C₁ -C₇)alkyls; or agroup COR₁₂ ;

R₃₅ is a piperid-4-yl which is unsubstituted or substituted in the1-position by a (C₁ -C₇)alkoxycarbonyl or by a (C₁ -C₇)alkyl; or apyrid-2-yl;

R₃₆ is a carboxyl; a (C₁ -C₇)alkoxycarbonyl; a benzyloxycarbonyl; or acarbamoyl which is free or substituted by R₃₈ and R₃₉ ;

R₃₇ is R₁₃ ; a (C₃ -C₇)cycloalkyl; a (C₁ -C₆)alkylene substituted byR24; a (C₂ -C₆)alkylene substituted by a hydroxyl or a (C₁ -C₇)alkoxy;or a (C₂ -C₆)alkylene substituted by an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls or by a protective group;

R₃₈ and R₃₉ are each independently a hydrogen; or a (C₁ -C₇)alkyl; R₃₉can also be a (C₁ -C₆)alkylene substituted by R₂₄ ; a (C₂ -C₆)alkylenesubstituted by a hydroxyl or a (C₁ -C₇)alkoxy; or a (C₂ -C₆)alkylenesubstituted by an amino which is free or substituted by one or two (C₁-C₇)alkyls or by a protective group;

X is SO₂ ; or CH₂ ;

m is 1 or, if R₆ is a halogen, a (C₁ -C₇)alkyl or a (C₁ -C₇)alkoxy, mcan also be 2, 3 or 4, or else (R₆)_(m) can be m substituents havingdifferent meanings selected from halogen; (C₁ -C₇)alkyl; and (C₁-C₇)alkoxy; and

p is an integer which can vary from 0 to 3; and their salts whereappropriate.

Advantageously, the invention relates to the compounds of formula (I) inwhich:

R₁ and R₂ are each independently a hydrogen; a halogen; a (C₁ -C₇)alkyl;a (C₁ -C₇)alkoxy; or a trifluoromethyl;

R₃ is a (C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl; a cyclohexyl substituted byone or two (C₁ -C₄)alkyls; or a phenyl which is unsubstituted ormonosubstituted or polysubstituted by a halogen, a (C₁ -C₇)alkyl, ahydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy or an acetoxy;

R₄ is an azido; a (C₁ -C₇)alkylsulfonamido; a phenylsulfonamido in whichthe phenyl is unsubstituted or monosubstituted or polysubstituted by ahalogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy oran acetoxy; a dimethylaminosulfonamido; a group NR₇ R₈ ; a group NR₉ R₁₀; a group NR₉ R₁₁ ; a heterocyclic radical R₁₂ ; a lactoylamino group; amandeloylamino group; an N'-(1-phenylethyl)ureido group; or anN'-(1-naphth-1-ylethyl)ureido group;

R₅ is hydrogen or has one of the meanings given for R₆ ;

R₆ is a halogen; a (C₁ -C₇)alkyl; a trifluoromethyl; a cyano; anaminomethyl in which the amino is free or substituted by one or two (C₁-C₇ )alkyls; a nitro; a group NR₉ R₁₁ ; a heterocyclic radical selectedfrom pyrrol-1-yl, Δ3-pyrrolin-1-yl, pyrrolidin-1-yl and morpholin-4-yl;a group OR₁₃ ; a group SR₁₃ ; a guanidino which is unsubstituted orsubstituted in the 3-position by one or two (C₁ -C₇)alkyls, a phenyl ora benzyl; a formyl; a (C₁ -C₇)alkylcarbonyl; a carbamoyl substituted byR₁₄ and R₁₅ ; a thiocarbamoyl which is free or substituted by one or two(C₁ -C₇)alkyls; a sulfamoyl substituted by R₁₆ and R₁₇ ; a carboxyl; a(C₁ -C₇)alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a (C₁-C₇)alkylsulfonamido; a phenylsulfonamido in which the phenyl isunsubstituted or monosubstituted or polysubstituted by a halogen, a (C₁-C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy or an acetoxy; or adimethylaminosulfonamido;

R₇ is a (C₁ -C₇)alkoxycarbonyl;

R₈ is a (C₁ -C₇)alkoxycarbonylamino; or an N-methyl-N-(C₁-C₇)alkoxycarbonylamino;

R₉ is a hydrogen; or a (C₁ -C₇)alkyl;

R₁₀ is a group CR₁₈ R₁₉ R₂₀ ; a group (CH₂)_(t) R₂₁ ; a group C(CH₃)(CH₂OH)₂ or C(CH₂ OH)₃ ; a non-aromatic C₃ -C₁₅ carbocyclic radical; aphenyl which is unsubstituted or monosubstituted or polysubstituted by ahalogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy oran acetoxy; a benzyl in which the phenyl is unsubstituted ormonosubstituted or polysubstituted by a halogen, a (C₁ -C₇)alkyl, ahydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy or an acetoxy; or a phenethyl inwhich the phenyl is unsubstituted or monosubstituted or polysubstitutedby a halogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxyor an acetoxy;

R₁₁ is a hydrogen; a (C₁ -C₁₂)alkyl; a (C₃ -C₇)cycloalkylmethyl; a groupOR₁₃ ; a formyl; a (C₁ -C₇)alkylcarbonyl; a (C₁ -C₇)alkylthiocarbonyl; a(C₃ -C₇)cycloalkylcarbonyl; a (C₃ -C₇)cycloalkylthiocarbonyl; a benzoylwhich is unsubstituted or monosubstituted or polysubstituted by ahalogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy oran acetoxy; a phenylacetyl in which the benzene ring is unsubstituted ormonosubstituted or polysubstituted by a halogen, a (C₁ -C₇)alkyl, ahydroxyl, a (C₁ -C₇)alkoxy, a benzyloxy or an acetoxy; apyridylcarbonyl; a thienylcarbonyl; a furylcarbonyl; apiperid-4-ylcarbonyl which is unsubstituted or substituted in the1-position by a (C₁ -C₇)-alkyl or by a protective group; a (C₁-C₇)alkoxycarbonyl; a phenoxycarbonyl; a phenoxythiocarbonyl; abenzyloxycarbonyl; a carbamoyl substituted by R₂₂ and R₂₃ ; athiocarbamoyl substituted by R₂₂ and R₂₃ ; a group CH₂ R₂₄ ; an ω-R₂₄(C₁ -C₆)alkylcarbonyl; or an ω-amino(C₁ -C₄)alkylcarbonyl in which theamino is free or substituted by one or two C₁ -C₇ -alkyls or by aprotective group;

R₁₂ is a morpholin-4-yl; a thiomorpholin-4-yl; an azetidin-1-yl which isunsubstituted, substituted in the 2-position by a carboxyl orsubstituted in the 3-position by an amino which is free or carries aprotective group; a perhydroazepin-1-yl; a piperazin-1-yl which isunsubstituted or substituted in the 4-position by R₂₅ ; a piperid-1-ylwhich is unsubstituted or substituted by R₂₆ ; a pyrrolidin-1-yl whichis unsubstituted or substituted by R₂₇ ; or a thiazolidin-3-yl which isunsubstituted or substituted by R₂₇ ;

R₁₃ is a hydrogen; a (C₁ -C₇)alkyl; a benzyl; an allyl; or atetrahydropyran-2-yl;

R₁₄ and R₁₅ are each independently hydrogen; or a (C₁ -C₇)alkyl; R₁₅ canalso be a (C₁ -C₇)alkyl substituted by a cyano, a trifluoromethyl or anamino which is free or substituted by one or two (C₁ -C₇)alkyls; a (C₃-C₇)cycloalkyl; a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a halogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁-C₇)alkoxy or a benzyloxy; or a group R₂₈ ;

or R₁₄ and R₁₅, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ;

R₁₆ and R₁₇ are each independently a hydrogen; or a (C₁ -C₇)alkyl; R₁₇can also be a (C₃ -C₇)cycloalkyl; or a group R₂₈ ;

or R₁₆ and R₁₇, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ;

R₁₈ is a (C₁ -C₇)alkyl; a phenyl; a benzyl; a cyclohexylmethyl; aphenethyl; an imidazol-4-ylmethyl which is free or carries a protectivegroup; an indol-3-yl-methyl which is free or carries a protective group;a hydroxymethyl which is free or carries a protective group; a2-hydroxyethyl which is free or carries a protective group; a1-hydroxyethyl which is free or carries a protective group; a4-hydroxybenzyl which is free or carries a protective group; amercaptomethyl which is free or carries a protective group; a2-mercaptoethyl which is free or carries a protective group; a2-methylthioethyl; a 2-methylsulfinylethyl; a 2-methylsulfonylethyl; a4-aminobutyl which is free or carries a protective group; a3-aminopropyl which is free or carries a protective group; acarboxymethyl which is free or carries a protective group; a2-carboxyethyl which is free or carries a protective group; acarbamoylmethyl; a 2-carbamoylethyl; a 3-guanidinopropyl which is freeor carries a protective group; or a non-aromatic C₃ -C₁₅ carbocyclicradical;

R₁₉ is hydrogen; R₁₉ can also be a (C₁ -C₇)alkyl if R₁₈ is a (C₁-C₇)alkyl;

or R₁₈ and R₁₉, together with the carbon atom to which they are bonded,form a non-aromatic C₃ -C₁₅ carbocycle;

R₂₀ is R₂₄ ; a group CH₂ OR₁₃ ; or an aminomethyl in which the amino isfree or substituted by one or two (C₁ -C₇)alkyls or by a protectivegroup;

R₂₁ is R₂₄ ; a group OR₁₃ ; a group NR₃₂ R₃₃ ; or a cyano;

R₂₂ and R₂₃ are each independently a hydrogen; or a (C₁ -C₇)alkyl; R₂₃can also be a (C₃ -C₇)cycloalkyl; a (C₂ -C₃)alkylene substituted by R₂₉; a group CR₁₈ R₁₉ R₂₀ ; a group CH₂ R₂₄ ; or a group C(CH₃)(CH₂ OH)₂ orC(CH₂ OH)₃ ;

or R₂₂ and R₂₃, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ; or acis-2,6-dimethylpiperid-1-yl;

R₂₄ is a carboxyl; a (C₁ -C₇)alkoxycarbonyl; a benzyloxycarbonyl; or acarbamoyl which is free or substituted by one or two (C₁ -C₇)alkyls;

R₂₅ is a (C₁ -C₇)alkyl; a phenyl; a benzyl; a formyl; a (C₁-C₆)alkylcarbonyl; a (C₁ -C₇)alkoxycarbonyl; or a benzyloxycarbonyl;

R₂₆ is R₂₄ ; an amino which is free or substituted by one or two (C₁-C₇)alkyls or by a protective group; a group OR₁₃ ; or a group CH₂ R₁₃ ;

R₂₇ is R₂₄ ; a group CH₂ R₂₄ ; a group CH₂ OR₁₃ ; or an aminomethyl inwhich the amino is free or substituted by one or two (C₁ -C₇)alkyls orby a protective group;

R₂₈ is a group CH(CH₂ OH)₂, CH(CH₃)CH₂ OH, C(CH₃)--(CH₂ OH)₂, C(CH₃)₂CH₂ OH, C(CH₂ OH)₃ or CH₂ CH₂ OH;

R₂₉ is a group R₂₄ ; a group OR₁₃ ; or a group NR₃₀ R₃₁ ;

R₃₀ and R₃₁ are each independently a hydrogen; or a (C₁ -C₇)alkyl;

or R₃₀ and R₃₁, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ;

R₃₂ and R₃₃ are each independently a hydrogen; or a (C₁ -C₇)alkyl; R₃₃can also be an acetyl; a phenyl; a benzyl; or a C₂ -C₃ -alkylenesubstituted by a group OR₁₃ or an amino which is free or substituted byone or two (C₁ -C₇)alkyls or by a protective group;

or R₃₂ and R₃₃, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₁₂ ;

X is SO₂ ; or CH₂ ;

m is 1 or, if R₆ is a halogen, a (C₁ -C₇)alkyl or a (C₁ -C₇)alkoxy, mcan also be 2, 3 or 4, or else (R₆)_(m) can be m substituents havingdifferent meanings selected from halogen; (C₁ -C₇)alkyl; and (C₁-C7)alkoxy; and

t is an integer which can vary from 2 to 10; and their salts whereappropriate.

If a compound according to the invention has one or more asymmetriccarbons, the invention includes all the optical isomers of thiscompound.

The salts of the compounds of formula (I) according to the presentinvention include those with mineral or organic acids which permit asuitable separation or crystallization of the compounds of formula (I),such as picric acid, oxalic acid or an optically active acid, forexample a mandelic acid or a camphosulfonic acid, and mineral or organicacids which form physiologically acceptable salts such as thehydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogenphosphate, maleate, fumarate, naphthalene-2-sulfonate andparatoluenesulfonate.

The salts of the compounds of formula (I) also include those withorganic or mineral bases, for example the salts of alkali metals oralkaline earth metals, such as the sodium, potassium and calcium salts,the sodium and potassium salts being preferred, or with an amine such astrometamol, or else those with arginine, lysine or any physiologicallyacceptable amine.

According to the present invention, halogen is understood as meaning anatom selected from fluorine, chlorine, bromine and iodine, preferablyfluorine or chlorine.

Protective groups for amine, hydroxyl, thiol or carboxyl groups areunderstood as meaning protective groups such as those described inProtective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wutts,published by John Wiley and Sons, 1991, and in Protective Groups inOrganic Chemistry, J. F. W. McOmie, published by Plenum Press, 1973.

According to the present invention, C₁ -C₇ -, C₁ -C₄ -, C₁ -C₆ -, C₂ -C₆-, C₁ -C₁₂ - or C₂ -C₁₀ -alkyl is understood as meaning a linear orbranched C₁ -C₇ -, C₁ -C₄ -, C₁ -C₆ -, C₂ -C₆ -, C₁ -C₁₂ - or C₂ -C₁₀-alkyl.

The non-aromatic C₃ -C₁₅ carbocyclic radicals include saturated orunsaturated, fused or bridged, monocyclic or polycyclic radicals,possibly terpene radicals. These radicals are optionally monosubstitutedor polysubstituted by a C₁ -C₄ -alkyl. The monocyclic radicals includecycloalkyls, for example cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclo-octyl and cyclododecyl. The polycyclic radicalsinclude for example norbornane and adamantane.

In the group CR₁₈ R₁₉ R₂₀, if R₁₈ and R₁₉, together with the carbon atomto which they are bonded, form a non-aromatic C₃ -C₁₅ carbocycle, saidcarbocycle is as defined for the corresponding radicals above.

The compounds of formula (I) in which R₁ is in the 5-position of theindol-2-one and R₂ is in the 6-position or is hydrogen are preferredcompounds.

The compounds of formula (I) in which R₁ is a chlorine atom or an ethoxygroup in the 5-position of the indol-2-one and R₂ is hydrogen or achlorine atom or a methyl group in the 6-position are preferredcompounds.

The compounds of formula (I) in which R₃ is a chlorophenyl, amethoxyphenyl or a cyclohexyl are preferred compounds.

The compounds of formula (I) in which R₄ is an amino group, a (C₁-C₁₂)alkylamino, a piperazin-1-yl substituted in the 4-position by a (C₂-C₁₀)alkyl group substituted by an amino, a group N(R₉)(CH₂)_(p) R₃₅, agroup N(R₉)(C₂ -C₁₀)alkyl-R₂₁ or a group N(R₉)CO(C₁ -C₄)alkyl-NR₃₂ R₃₃are preferred compounds.

The compounds of formula (I) in which R₅ is either hydrogen or a methoxygroup in the 2-position and R₆ in the 4-position is a benzamido which isunsubstituted or substituted by a methoxy, a carbamoyl substituted byR₁₄ and R₁₅, or a C₁ -C₇ -dialkylureido, or R₅ and R₆ together with thephenyl to which they are bonded, form a group ##STR8## with the provisothat X is --SO₂ --, are preferred compounds.

Very particularly preferred compounds are those of the formula ##STR9##in which:

R_(1a) is an ethoxy or a chlorine;

R_(2a) is hydrogen, a chlorine or a methyl group;

R_(3a) is a chlorophenyl, a methoxyphenyl or a cyclohexyl;

R_(4a) is an amino; a (C₁ -C₁₂)alkylamino; a piperazin-1-yl radicalsubstituted in the 4-position by a (C₂ -C₁₀)-alkylene group substitutedby an amino; a group N(R₉)--(CH₂)_(p) R₃₅ ; a group N(R₉)(C₂-C₁₀)alkyl-R₂₁ ; or a group N(R₉)CO(C₁ -C₄)alkyl-NR₃₂ R₃₃ ;

R_(5a) is hydrogen or a 2-methoxy;

R_(6a) is a benzamido in which the phenyl is unsubstituted orsubstituted by a methoxy; a group CONR₁₄ R₁₅ ; or an N',N'-di(C₁-C₇)alkylureido group;

or R_(5a) and R_(6a) together with the phenyl to which they are bonded,form a group ##STR10## with the proviso that X is SO₂ ; and thesubstituents X, R₉, R₁₄, R₁₅, R₂₁, R₃₂, R₃₃ and R₃₅ are as defined abovefor the compounds of formula (I); and their salts.

The following abbreviations are used in the description and in theExamples:

DCM: dichloromethane

Ether: diethyl ether

Iso ether: diisopropyl ether

CCl₄ : carbon tetrachloride

MeOH: methanol

EtOH: ethanol

AcOEt: ethyl acetate

DMF: dimethylformamide

THF: tetrahydrofuran

DIPEA: diisopropylethylamine

NEt₃ : triethylamine

DBU: 1,8-diazabicyclo 5.4.0!undec-7-ene

AcOH: acetic acid

HCl: hydrochloric acid

TFA: trifluoroacetic acid

NaCl: sodium chloride

Boc: tert-butoxycarbonyl

(Boc)₂ O: di-tert-butyl dicarbonate

Z: benzyloxycarbonyl

Bz: benzyl

Me, OMe: methyl, methoxy

Et, OEt: ethyl, ethoxy Pr, iPr: n-propyl, isopropyl

Bu, iBu, tBu: butyl, isobutyl, tert-butyl

Ms: mesyl

BOP: benzotriazol-1-yloxytris(dimethylaminophosphonium)hexafluorophosphate

Lawesson's reagent:2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide

Silica H: 60H silica gel marketed by MERCK (DARMSTADT)

M.p.: melting point

RT: room temperature

NMR: nuclear magnetic resonance

s: singlet

bs: broad singlet

d: doublet

t: triplet

qd: quadruplet

m: unresolved signals

mt: multiplet

t of d: triplet of doublets

d of d: doublet of doublets

sep: septuplet

The present invention further relates to a method of preparing thecompounds according to the invention, which comprises:

1) reacting a halide of the formula ##STR11## in which Hal is a halogenatom, preferably chlorine or bromine, and R'₅ and R'₆ are respectivelyeither R₅ and R₆ as defined above for (I), or precursor groups of R₅ andR₆, with a compound of the formula ##STR12## in which R'₁, R'₂ and R'₄are respectively either R₁, R₂ and R₄ as defined for (I), or precursorgroups of R₁, R₂ and R₄, and R₃ is as defined for (I); and

2) either, if R'₁ ═R₁, R'₂ ═R'₂, R₄ ═R₄, R'₅ ═R₅ and R'₆ ═R₆, isolatingthe resulting compound of formula (I);

3) or, if any one of the groups R'₁, R'₂, R'₄, R'₅ and/or R'₆ isrespectively a precursor group of R₁, R₂, R₄, R5 and/or R₆, subjectingthe compound obtained in step 1) to a subsequent treatment in order toprepare the compound of formula (I) by converting any one of the groupsR'₁, R'₂, R'₄, R'₅ and/or R'₆ to R₁, R₂, R₄, R₅ and/or R₆ respectively;and

4) if appropriate, converting the compound obtained in step 2) or step3) to one of its salts.

A compound carrying a substituent R'₁, R'₂, R'₄, R'₅ and/or R'₆, whichare precursors of R₁, R₂, R₄, R₅ and/or R₆, is called a compound (I').

The reaction of step 1) is carried out in an anhydrous solvent such asDMF or THF, in the presence of a metal hydride such as, for example,sodium hydride, or in the presence of an alcoholate such as potassiumtert-butylate. 1,3-Dihydroindol-2-one derivatives of formula (II) can beprepared by the methods described in patents ZA 83 09532 and 85 04765and patent GB 1 125 671.

1,3-Dihydroindol-2-one derivatives substituted in the 3-position bynitrogen-containing groups can also be prepared by methods well known tothose skilled in the art, such as those described in the followingpublications:

Farm. Zh. (Kiev), 1976, 5, 30-33.

Khim-Farm. Zh., 1979, 13 (11), 45-49.

J. Pharm. Sci., 1975, 64 (4), 639-642.

Chem. Pharm. Bull., 1978, 26 (9), 2866-2873.

J. Org. Chem., 1964, 29, 1206.

More particularly, the 1,3-dihydroindol-2-ones (II) can be obtained byreacting a 3-halogeno-1,3-dihydroindol-2-one compound of the formula##STR13## with a compound of the formula

    H--R'.sub.4                                                (VI)

in which formulae R'₁, R'₂, R₃ and R'₄ are as defined above and Hal is ahalogen, preferably chlorine or bromine. The reaction can be carried outin the presence of a base such as DIPEA or triethylamine, which behavesas an acid acceptor, or by using an excess of the compound (VI).

The 3-halogeno-1,3-dihydroindol-2-ones (V) are obtained by any one ofthe various methods described in the literature.

For example, a compound of the formula ##STR14## in which R'₁, R'₂ andR₃ are as defined above, is converted directly to a3-halogeno-1,3-dihydroindol-2-one compound (V) by means of ahalogenating agent such as bromine (by the method described in Farm. Zh.(Kiev), 1976, 5, 30-33) or such as N-chlorosuccinimide in a solvent likeCCl₄.

The compounds of formula (VII) are prepared according to J. Org. Chem.,1968, 33 (4), 1640-1643. In particular, a compound of formula (VII) inwhich R₃ is an unsubstituted or substituted cyclohexylmethyl or benzylcan be prepared according to J. Med. Chem., 1965, 8, 626-637.

According to another example of the preparation of the compounds offormula (V), an isatin derivative of the formula ##STR15## is reactedwith a compound of the formula

    (IX) R.sub.3 M or R.sub.3 MgBr                             (X)

in which formulae R'₁, R'₂ and R₃ are as defined above and M is areactive metal substituent such as lithium, under anhydrous conditions,the intermediate obtained is hydrolyzed to give a3-hydroxy-1,3-dihydroindol-2-one compound of the formula ##STR16## andthe latter compound is then converted to the corresponding3-halogeno-1,3-dihydroindol-2-one compound (V) by reaction with thionylchloride or a similar halogenating agent.

It is also possible to prepare a compound of formula (XI) by oxidizing acompound of formula (VII) with air in the presence of a base such assodium hydride, and in the presence of dimethyl disulfide.

According to another method of preparing the compounds of formula (II),a compound of formula (XI) is reacted with methanesulfonyl chloride inthe presence of a base such as, for example, triethylamine, in ananhydrous solvent such as THF; the resulting mesylate is converted tothe 1,3-dihydroindol-2-one of formula (II) by reaction with a compoundof formula (VI).

Preferably, to prepare a compound of formula (II) in which R'₄ is azido,sodium azide is reacted with a compound (V); the reaction is carried outin acetonitrile under reflux or according to the method described by Y.Tamura et al. in Chem. Pharm. Bull., 1978, 26 (9), 2866-2873.

A compound of formula (II) in which R'₄ is an amino can be prepared byreacting a compound of formula (II) in which R'₄ is azido withpropane-1,3-dithiol in the presence of a base such as triethylamine,according to the method described by H. Bayley et al. in TetrahedronLetters, 1978, 39, 3633-3634.

This method is particularly preferred for the preparation of a compoundof formula (II) in which R'₄ is an amino and R'₁ in the 5-position is a(C₁ -C₇)-alkoxy.

A compound (II) in which R'₄ is a group NR₇ R₈ is prepared by reacting acompound of the formula

    R.sub.7 --N═R.sub.8                                    (XII)

    i.e.:

    AlkOOC--N═N--COOAlk

in which Alk is a (C₁ -C₇)alkyl, with a compound (VII); the reaction iscarried out in an anhydrous solvent such as THF, in the presence of abase such as lithium diisopropylamide.

A compound of formula (II) in which R'₄ is an amino acid residue (R'₄═N(R₉)CR₁₈ R₁₉ R₂₀) is prepared by reacting an amino acid or aderivative thereof, optionally protected by the protective groupsconventionally used in peptide synthesis, of the formula ##STR17## witha compound (V).

The amino acids which are not commercially available are preparedaccording to the synthesis of Strecker, Ann., 1850, 75, 27, or accordingto the synthesis of H. T. Bucherer et al., J. Pract. Chem., 1934, 141,5, followed by hydrolysis to give the amino acids; for example,2-aminoadamantane-2-carboxylic acid is prepared according to H. T.Nagasawa et al., J. Med. Chem., 1973, 16 (7), 823.

α-Amino-1-adamantylacetic and α-amino-2-adamantylacetic acids areprepared according to B. Gaspert et al., Croatica Chemica Acta, 1976, 48(2), 169-178.

2-Aminonorbornane-2-carboxylic acid is prepared according to H. S. Tageret al., J. Am. Chem. Soc., 1972, 94, 968.

α-Aminocycloalkylcarboxylic acids are prepared according to J. W. Tsanget al., J. Med. Chem., 1984, 27, 1663.

R- and S-cyclopentylglycines are prepared according to European patentapplication EP 477 049.

R- and S-cyclohexylglycines are prepared according to Rudman et al., J.Am. Chem. Soc., 1952, 74, 551.

R- and S-cyclohexylglycines can also be prepared by the catalytichydrogenation of R- and S-phenylglycines.

α-Aminocycloalkylcarboxylic acids having the R or S configuration canalso be prepared by stereospecific enzymic hydrolysis of thecorresponding racemic N-acetylated derivatives according to J. Hill etal., J. Org. Chem., 1965, 1321.

A compound of formula (II) in which R'₄ is a group N(R₉)(CH₂)_(p) R₃₅ isprepared by reacting a compound of the formula ##STR18## with a compound(V).

The compounds of formula (XV) are known or are prepared by knownmethods. For example, the compounds of formula (XV) in which R₃₅ is apiperid-4-yl substituted in the 1-position by a Boc are preparedaccording to Prugh J. D. et al., Synthetic Communications, 1992, 22, 16,2357-2360, if p=1; if p=2 or 3, the method described in J. Med. Chem.,1989, 32, 391-396, or the method described in Scheme 1, is applied.##STR19##

A compound of formula (II) in which R'₄ is a group N(R₉)CH₂ R₃₆ in whichR₃₆ is a (C₁ -C₇)alkoxycarbonyl or a benzyloxycarbonyl is prepared byreacting a compound of the formula ##STR20## in which R₃₆ is a (C₁-C₇)alkoxycarbonyl or, respectively, a benzyloxycarbonyl with a compound(V). By known methods, such a compound is used to prepare a compound offormula (II) in which R'₄ is a group N(R₉)CH₂ COOH, which, by reactionwith a compound of the formula HNR₃₈ R₃₉ according to the appropriatetechniques of amide coupling, makes it possible to obtain a compound offormula (II) in which R'₄ is a group N(R₉)CH₂ CONR₃₈ R₃₉.

The same methods described above are used to prepare the compounds offormula (II) in which R'₄ is a group N(R₉)--(C₂ -C₁₀)alkyl-R₃₆ in whichR₃₆ is a (C₁ -C₇)alkoxycarbonyl, a benzyloxycarbonyl or a carbamoylsubstituted by R₃₈ and R₃₉.

A compound of formula (II) in which R'₄ is a group N(R₉)(C₂-C₁₀)alkyl-OR₃₇ is prepared by reacting a compound of the formula##STR21## with a compound (V).

The compounds of formula (XVIII) are known or are prepared by knownmethods.

A compound of formula (II) in which R'₄ is a group N(R₉)(C₂-C₁₀)alkyl-NR₃₂ R₃₃ is prepared by reacting a compound of the formula##STR22## with a compound (V).

The compounds of formula (XIX) are known or are prepared by knownmethods. For example, the compounds of formula (XIX) are preparedaccording to the methods described in J. Med. Chem., 1989, 32, 391-396,in Synthesis, 1982, 404-405, in J. Am. Chem. Soc., 1946, 68, 10-14, orin patent EP-0429344. The compounds of formula (XIX) in which R₃₃ isother than a protective group can also be prepared by following thedifferent steps of the method described in Scheme 2. ##STR23##

To prepare a compound of formula (II) in which R'₄ is a group N(R₉)(C₂-C₁₀)alkyl-S(C₁ -C₇)alkyl, a compound of the formula ##STR24## isreacted with a compound (V). The compounds of formula (XVIII') are knownor are prepared by known methods. The compounds of formula (II) in whichR'₄ is a group N(R₉)(C₂ -C₁₀)alkyl-SO(C₁ -C₇)alkyl or a group N(R₉)(C₂-C₁₀)alkyl-SO₂ (C₁ -C₇)alkyl are prepared, according to methods known tothose skilled in the art, from the compounds of formula (II) in whichR'₄ is a group N(R₉)(C₂ -C₁₀)alkyl-S(C₁ -C₇)alkyl.

Compounds of formula (II) in which R'₄ is a (C₁ -C₇)alkylamino or a (C₁-C₁₂)alkylamino can also be prepared by reacting a compound of formula(II) in which R'₄ is an amino group with an aldehyde or a ketone in anacid medium, in the presence of a reducing agent such as sodiumcyanoborohydride; an identical reaction is used to prepare the compoundsof formula (II) in which R'₄ is a dialkylamino in which the alkyls areidentical or different, one of the alkyls being C₁ -C₇ and the other C₁-C₁₂.

The compounds of formula (II) in which R'₄ is an amino group substitutedby an optionally substituted benzyl can also be prepared by reacting anoptionally substituted benzyl chloride with a compound of formula (II)in which R'₄ is an amino group or an alkylamino group in which the alkylis C₁ -C₇.

To prepare the compounds of formula (II) in which R'₄ is an amino groupsubstituted by a cycloalkylmethyl in which the cycloalkyl is C₃ -C₇ oran optionally substituted phenethyl, it is also possible to react acompound of formula (II) in which R'₄ is an amino group with acycloalkylcarboxaldehyde in which the cycloalkyl is C₃ -C₇ or,respectively, an optionally substituted phenylacetaldehyde in an acidmedium, in the presence of a reducing agent such as sodiumcyanoborohydride.

A compound of formula (II) in which R'₄ is a group ω-R₃₂ R₃₃ N(C₁-C₄)alkylCON(R₉)-- is prepared by reacting a halogeno(C₁-C₄)alkylcarbonyl halide such as bromoacetyl bromide, 3-chloropropionylchloride, 4-chlorobutyryl chloride or 5-chlorovaleryl chloride, forexample, with a compound of formula (II) in which R'₄ is a group R₉NH--; then, reaction of the resulting intermediate with a compound HNR₃₂R₃₃ gives the compound of formula (II) designated above. In particular,reaction of a compound of formula (II) in which R'₄ is a group R₉ NH--with acryloyl chloride in the presence of a base such as pyridine,followed by reaction of the resulting intermediate with a compound HNR₃₂R₃₃, gives a compound of formula (II) in which R'₄ is a group N(R₉)COCH₂CH₂ NR₃₂ R₃₃.

Some of the compounds of formula (VII) and some of the compounds offormula (V) are novel and form a further subject of the presentinvention.

Thus the compounds of the formula ##STR25## and the compounds of theformula ##STR26## in which:

R_(I) and R_(II) are each independently a hydrogen, a halogen, a (C₁-C₇)alkyl, a (C₁ -C₇)alkoxy, a trifluoromethyl, a nitro, an amino, ahydroxyl or a benzyloxy;

R_(lIII) is a phenyl monosubstituted or polysubstituted by a halogen, a(C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇)-alkoxy, a benzyloxy or an acetoxy;and

Hal is a halogen, are novel and form part of the invention.

Likewise, some of the compounds of formula (II) are novel and form asubject of the present invention.

Thus the compounds of the formula ##STR27## in which:

R_(I), R_(II) and R_(III) are as defined above for (V') and (VII');

R_(IV) is an azido, an amino, a 2,2-dimethylhydrazino group, a group NR₇R₈, a group NR₉ R₁₀ or NR₉ R_(XI), a heterocyclic radical R₁₂ or apiperazin-1-yl radical substituted in the 4-position by a (C₂-C₁₀)alkylene group substituted by an amino group which is free orcarries a protective group;

R_(XI) is a (C₁ -C₁₂)alkyl, a (C₃ -C₇)cycloalkylmethyl, a group OR₁₃, agroup CH₂ R₃₆ or a group ω-R₃₂ R₃₃ N(C₁ -C₄)-alkylcarbonyl; and

₇, R₈, R₉, R₁₀, R₁₂, R₁₃, R₃₂, R₃₃ and R₃₆ are as defined above for (I),are novel and form part of the invention.

The benzenesulfonyl halides (III) are prepared by known methods.

Thus, for example, 4-dimethylaminobenzenesulfonyl chloride is preparedaccording to C. N. Sukenik et al., J. Amer. Chem. Soc., 1977, 99,851-858. More generally, the benzenesulfonyl halides (III) substitutedby a dimethylamino group are known or are prepared by known methods;p-benzyloxybenzenesulfonyl chloride is prepared according to Europeanpatent application EP 229 566.

The alkoxybenzenesulfonyl chloride is prepared from the sodiumalkoxybenzenesulfonate, which is itself prepared by reacting an alkylhalide with sodium hydroxybenzenesulfonate.

2,4-Dimethoxybenzenesulfonyl chloride is prepared according to J. Am.Chem. Soc., 1952, 74, 2008.

The benzenesulfonyl halides of the formula ##STR28## in which:

Alk is a (C₁ -C₇)alkyl;

Y is O or S; and

R_(VI) is a (C₁ -C₇)alkyl, an allyl or a benzyl, are prepared accordingto D. Hofmann et al. in Liebigs Ann. Chem., 1982, 287-297.

Trimethylsilyl chlorosulfonate is reacted with benzene compoundscarrying the substituents YR_(VI) and OAlk in the 1,3-position, in asolvent such as DCM, at RT. This is followed by application of themethod of R. Passerini et al. in Gazz. Chim. Ital., 1960, 90, 1277-89,and then by neutralization, for example with alkali metal carbonate,after which the product is reacted with a halide, such as POCl₃, to givethe desired benzenesulfonyl halide.

The benzenesulfonyl halides (III) substituted by a (C₁-C₇)alkoxycarbonyl, a phenoxycarbonyl, a benzyloxycarbonyl, a (C₁-C₇)alkylthio or a benzylthio are prepared according to Col. Czechoslov.Chem. Commun., 1984, 49, 1184, from an aniline derivative substituted bythe same group, said aniline derivative itself being obtained from thecorresponding nitro derivative.

The nitrobenzoic acid derivatives are known; an appropriateesterification reaction with this acid gives the corresponding alkyl andphenyl esters.

The benzenedisulfonyl dihalides (III, R'₆ ═SO₂ Hal) are known or areprepared by known methods. For example,2,4.dimethoxybenzene-1,5-disulfonyl dichloride is described by R. J. W.Cremlyn in J. Chem. Soc. C, 1969, 1341-1345.

The benzenesulfonyl halides (III) in which R'₆ in the 4-position is asulfamoyl substituted by R₁₆ and R₁₇ (R'₆ ═SO₂ NR₁₆ R₁₇) and R'₅ in the2-position is a (C₁ -C₇)alkoxy can be prepared by the following method:3-Alkoxy-4-nitrobenzenesulfonyl halides are prepared by reactingchlorosulfonic acid with 2-alkoxynitrobenzene compounds and theresulting sulfonyl chloride is reacted with compounds HNR₁₆ R₁₇. Thecorresponding benzenesulfonyl halides are obtained according to Col.Czechoslov. Chem. Commun., 1984, 49, 1184, from the aniline derivativessubstituted by the same group, said aniline derivatives themselves beingobtained from the corresponding nitro derivatives.

The benzenesulfonyl halide (III) in which R'₆ in the 4-position is anN',N'-diethylureido group R'₆ ═NHCON(Et)₂ ! can be prepared by reactingchlorosulfonic acid with N',N'-diethyl-N-phenylurea, which is itselfobtained by reacting aniline with diethylcarbamoyl chloride.

4-(Morpholin-4-yl)benzenesulfonyl chloride is prepared according to themethod described in Arzneim.-Forsch./Drug Res., 1994, 44 (I), no. 4,501-509.

The benzenesulfonyl halide of formula (III) in which R'₅ and R'₆,together with the phenyl to which they are bonded, form a group##STR29## is prepared by reacting chlorosulfonic acid with a compound ofthe formula ##STR30## in which R₃₄ is as defined for (I).

The compounds of formula (XXI) in which R₃₄ is a formyl or a (C₁-C₇)alkylcarbonyl are obtained by reacting formic acid in aceticanhydride or, respectively, by reacting an appropriate anhydride or anappropriate acid chloride, in the presence of an amine such astriethylamine, with indoline. Likewise, reaction of a C₁ -C₇ -alkyl orphenyl chloroformate with indoline in the presence of a base such aspyridine gives the compounds of formula (XXI) in which R₃₄ is a (C₁-C₇)alkoxycarbonyl or a phenoxycarbonyl.

Reaction of a carbamoyl chloride substituted by two (C₁ -C₇)alkyls withindoline in the presence of a base such as pyridine gives the compoundsof formula (XXI) in which R₃₄ is a carbamoyl substituted by two (C₁-C₇)alkyls.

Reaction of a compound R₁₂ H with a compound of formula (XXI) in whichR₃₄ is a phenoxycarbonyl gives a compound of formula (XXI) in which R₃₄is a group COR₁₂.

The benzyl halides of formula (IV) are known or are prepared by knownmethods.

By way of example, publications may be cited which describe thefollowing halogenomethylbenzene derivatives:

1,2,4- 4,2,1- or 2,4,1-(chloromethyl),(methyl), (methoxy)benzene : Bull.Soc. Chim. France, 1937, 4, 1092.

2-chloromethyl-1,3-dimethoxybenzene: Chem. Listy, 1953, 47, 601-612.

1-bromomethyl-2-methoxy-4-nitrobenzene: Sci. Sinica (Peking), 1962, 11,483-498.

1-bromomethyl-2-methyl-4-nitrobenzene: Pharmazie, 1969, 24 (1), 29-32.

1-bromomethyl-2-methoxy-4-nitrobenzene: Bull. Soc. Chim. France, 1962,2255.

1-bromomethyl-4-methoxy-2-nitrobenzene: Zh. Obshch. Khim., 1963, 33 (8),2792-2793.

methyl 4-bromomethyl-3-methoxybenzoate: European patent application EP179 619.

ethyl 2-bromomethyl-6-methoxybenzoate: J. Org. Chem., 1983, 48,3439-3444.

ethyl 2-bromomethyl-4,5-dimethoxybenzoate and ethyl2-bromomethyl-3,4-dimethoxybenzoate: J. Org. Chem., 1968, 33, 494.

methyl 4-bromomethyl-2-methoxybenzoate: Bull. Soc. Chim. France, 1962,2255.

1-bromomethyl-4-cyano-2-methoxybenzene and4-aminomethyl-1-bromomethyl-2-methoxybenzene: J. Med. Chem., 1990, 33,2437-2451.

In general, the halogenomethylbenzene derivatives can be prepared byreacting N-bromosuccinimide with the corresponding methylbenzenederivatives. The reaction is carried out in a solvent such as carbontetrachloride, in the presence of dibenzoyl peroxide. It is alsopossible to prepare a halogenomethylbenzene derivative from acorresponding hydroxymethylbenzene derivative by reaction withphosphorus tribromide in ether.

According to another method, the halogenomethylbenzene derivatives offormula (IV) can be prepared from the corresponding alcohol by reactionwith thionyl chloride to give a methylbenzene chloride.

For certain meanings of the substituents R₁, R₂, R₄, R₆ and/or R₅, thecompounds (I) according to the invention can be prepared from aprecursor of formula (I') substituted by a group R'₁, R'₂, R'₄, R'₆and/or R'₅, called a precursor group of R₁, R₂, R₄, R₆ and/or R₅, usingmethods known to those skilled in the art.

The following description relates to the preparation of the compounds offormula (I) carrying substituents R₁, R₄ and/or R₆ ; the same methodsare applied to the preparation of the compounds in which thesubstituents R₂ and/or R₅ have the meanings indicated for R₁ and/or R₆.

The compounds of formula (I) in which R₄ is a group N(R₉)(CH₂)_(p) R₃₅in which R₃₅ is a piperid-4-yl unsubstituted in the 1-position areobtained by carrying out a conventional deprotection reaction on thecompounds of formula (I) in which R₃₅ is a piperid-4-yl substituted inthe 1-position by a protective group.

The compounds of formula (I) in which R₄ is a group N(R₉)CH₂ R₃₆ inwhich R₃₆ is a carboxyl can be prepared from the corresponding compoundsof formula (I) in which R₃₆ is a (C₁ -C₇)alkoxycarbonyl or abenzyloxycarbonyl. Then, reaction of a compound of formula (I) in whichR₄ is a group N(R₉)CH₂ COOH with a compound of the formula HNR₃₈ R₃₉,according to the appropriate techniques of amide coupling, gives thecompounds of formula (I) in which R₄ is a group N(R₉)--CH₂ CONR₃₈ R₃₉.

The same methods described above can be used to prepare the compounds offormula (I) in which R₄ is a group N(R₉)(C₂ -C₁₀)alkyl-R₃₆ in which R₃₆is a carboxyl or a group CONR₃₈ R₃₉.

The compounds of formula (I) in which R₄ is a group N(R₉)(C₂-C₁₀)alkyl-NR₃₂ R₃₃ in which NR₃₂ R₃₃ is a piperazin-1-yl substituted inthe 4-position by a (C₁ -C₇)alkyl can be prepared either directly by themethod according to the invention, starting from the correctlysubstituted compounds of formula (II), or by reaction of thecorresponding compounds of formula (I) in which NR₃₂ R₃₃ is apiperazin-1-yl unsubstituted in the 4-position with an aldehyde or aketone in an acid medium, in the presence of a reducing agent such assodium cyanoborohydride.

The compounds (I) in which R₄ and/or R₆ are a (C₁ -C₇)alkylsulfonamido,a phenylsulfonamido or a dimethylaminosulfonamido are obtained byreacting an alkylsulfonyl halide in which the alkyl is C₁ -C₇, abenzenesulfonyl halide or, respectively, a dimethylsulfamoyl halide witha compound (I) in which R₄ and/or R₆ are an amino group.

The compounds (I) in which R₄ is a lactoylamino or mandeloylamino groupare obtained by reacting a lactic acid or, respectively, a mandelic acidwith a compound (I) in which R₄ is an amino group, according to theappropriate techniques of amide coupling.

The compounds (I) in which R₄ is an N'-(1-phenylethyl)ureido orN'-(1-naphth-1-ylethyl)ureido group are obtained by reacting anα-methylbenzyl isocyanate or, respectively, a naphth-1-ylethylisocyanate with a compound (I) in which R₄ is an amino group.

The compounds (I) in which R₄ and/or R₆ are a group NR₉ R₁₁, R₁₁ being aformyl or a (C₁ -C₇)alkylcarbonyl, a (C₁ -C₇)cycloalkylcarbonyl, anoptionally substituted benzoyl, a phenacetyl in which the benzene ringis optionally substituted, a pyridylcarbonyl, a thienylcarbonyl, afurylcarbonyl or a piperid-4-ylcarbonyl, are obtained by reacting formicacid in acetic anhydride or, respectively, by reacting the appropriateanhydride or the appropriate acid chloride with a compound (I) in whichR₄ and/or R₆ are a group R₉ NH--, in the presence of an amine such astriethylamine.

The compounds (I) in which R₄ and/or R₆ are a group NR₉ R₁₁, R₁₁ being a(C₁ -C₇)alkoxycarbonyl, a phenoxycarbonyl or a benzyloxycarbonyl, areobtained by reacting a C₁ -C₇ -alkyl, phenyl or, respectively, benzylchloroformate with a compound (I) in which R₄ and/or R₆ are a group R₉NH--.

Likewise, reaction of a phenoxythiocarbonyl chloride with a compound offormula (I) in which R₄ and/or R₆ are a group R₉ NH-- gives a compoundof formula (I) in which R₄ and/or R₆ are a group NR₉ R₁₁ in which R₁₁ isa phenoxythiocarbonyl.

A compound of formula (I) in which R₄ and/or R₆ are a group N(R₉)CONH₂or N(R₉)CSNH₂ is prepared by reacting ammonia with a compound of formula(I) in which R₄ and/or R₆ are a group NR₉ R₁₁ in which R₁₁ is aphenoxycarbonyl or a phenoxythiocarbonyl.

It is also possible to prepare compounds of formula (I) in which R₄and/or R₆ are a ureido (NR₉ --CONR₂₂ R₂₃) or a thioureido (NR₉ CSNR₂₂R₂₃) by reacting a compound NHR₂₂ R₂₃ with a compound (I) in which R₄and/or R₆ are a group NR₉ R₁₁ in which R₁₁ is a phenoxycarbonyl or,respectively, a phenoxythiocarbonyl.

It is also possible to prepare compounds of formula (I) in which R₄and/or R₆ are a ureido (NR₉ --CONR₂₂ R₂₃) or a thioureido (NR₉ CSNR₂₂R₂₃) by reacting a carbamoyl chloride (ClCONR₂₂ R₂₃) or, respectively, athiocarbamoyl chloride (ClCSNR₂₂ R₂₃) with a compound of formula (I) inwhich R₄ and/or R₆ are a group R₉ NH--.

A compound (I) in which R₄ and/or R₆ are a group NR₉ R₁₁ in which R₁₁ isa (C₁ -C₇)alkylcarbamoyl can also be prepared by reacting a C₁ -C₇-alkyl isocyanate with a compound (I) in which R₄ and/or R₆ are a groupR₉ NH--.

It is also possible to prepare a compound (I) in which R₄ and/or R₆ area group N(R₉)CONR₂₂ R₂₃ or N(R₉)CSNR₂₂ R₂₃ in which R₉ is a (C₁-C₇)alkyl by reacting a base such as sodium hydride with a compound (I)in which R₄ and/or R₆ are a group NHCONR₂₂ R₂₃ or NHCSNR₂₂ R₂₃ and thenreacting the product with a (C₁ -C₇)alkyl halide.

A compound (I) in which R₄ and/or R₆ are a thioureido can also beprepared by reacting Lawesson's reagent with a compound (I) in which R₄and/or R₆ are the corresponding ureido.

A compound (I) in which R₄ and/or R₆ are a group NHCO(CH₂)₂ CO₂ H orNHCO(CH₂)₃ CO₂ H can be prepared by reacting an anhydride, such assuccinic anhydride or glutaric anhydride, with a compound (I) in whichR₄ and/or R₆ are an amino. If appropriate, the resulting acid isconverted to an ester or an amide.

A compound of formula (I) in which R₄ and/or R₆ are a group ω-R₃₂ R₃₃N(C₁ -C₄)alkylCON(R₉)-- can be prepared by reacting a halogeno(C₁-C₄)alkylcarbonyl halide such as bromoacetyl bromide, 3-chloropropionylchloride, 4-chlorobutyryl chloride or 5-chlorovaleryl chloride, forexample, with a compound of formula (I) in which R₄ and/or R₆ are agroup R₉ NH--; then, reaction of the resulting intermediate with acompound HNR₃₂ R₃₃ gives the compound of formula (I) designated above.

It is possible to prepare a compound of formula (I) in which R₄ is anamino group by reacting a solution of HBr in AcOH with a compound (I) inwhich R₄ is a group NR₉ CO₂ Me.

The compounds of formula (I) in which R₁ and/or R₆ are a (C₁ -C₇)alkoxycan be prepared directly by the method according to the invention,starting from the correctly substituted compounds of formula (II), (III)or (IV).

The compounds (I') in which R'₁ and/or R₆ are a hydroxyl can also beused to prepare compounds (I) in which R₁ and/or R₆ are a (C₁ -C₇)alkoxyby reaction with a C₁ -C₇ -alkyl halide in the presence of a base suchas a metal hydride or an alkali metal or alkaline earth metal carbonatelike K₂ CO₃ or Cs₂ CO₃, in a solvent such as THF or DMF.

The compounds (I') in which R'₁ and/or R₆ are a hydroxyl can be obtainedby the catalytic hydrogenation of a compound of formula (I') in whichR'₁ and/or R₆ are a benzyloxy, for example in the presence ofpalladiumon-charcoal. These compounds can also be prepared fromanalogous compounds of formula (I') in which R'₁ and/or R₆ are an aminogroup by using the method described in J. Org. Chem., 1977, 42, 2053.

A compound of formula (I) in which R₆ is a nitro group can be used toobtain a compound (I) in which R₆ is an amino group by catalytichydrogenation, for example in the presence of platinum oxide or Raneynickel, or by chemical reduction, for example in the presence of tin oriron in an acid medium; other compounds in which the amino group issubstituted can then be prepared using reactions well known to thoseskilled in the art.

To prepare compounds of formula (I) in which R₆ is a (C₁ -C₇)alkylaminoor a (C₁ -C₁₂)alkylamino, a compound of formula (I) in which R₆ is anamino group is reacted with an aldehyde or a ketone in an acid medium,in the presence of a reducing agent such as sodium cyanoborohydride; anidentical reaction is used to prepare the compounds (I) in which R₆ is adialkylamino in which the alkyls are identical or different, one of thealkyls being C₁ -C₇ and the other C₁ -C₁₂.

The compounds of formula (I) in which R₆ is a Δ3-pyrrolin-1-yl group areprepared by reacting cis-1,4-dichlorobut-2-ene, under an inertatmosphere, with the compounds of formula (I) in which R₆ is an aminogroup, in the presence of a base such as triethylamine. The compounds offormula (I) in which R₆ is a pyrrolidin-1-yl group are then prepared byhydrogenation.

The reaction of cis-1,4-dichlorobut-2-ene with the compounds (I) inwhich R₆ is an amino group can also be carried out in air in thepresence of a base such as Na₂ CO₃ ; under these conditions, it resultsin the formation of a mixture of a compound of formula (I) in which R₆is a Δ3-pyrrolin-1-yl group and a compound of formula (I) in which R₆ isa pyrrol-1-yl group, which can be separated by chromatography.

To prepare the compounds of formula (I) in which R₆ is a group R₉ NH--substituted by a (C₃ -C₇)-cycloalkylmethyl, a compound of formula (I) inwhich R₆ is a group R₉ NH-- is reacted with a cycloalkylcarboxaldehydein which the cycloalkyl is C₃ -C₇, in an acid medium, in the presence ofa reducing agent such as sodium cyanoborohydride.

If R₆ is an amino group, it is also possible to perform a nitrosation,for example in the presence of nitrous acid or sodium nitrite, in orderto prepare a compound (I') in which R'₆ is a diazonium salt; thecompounds (I) according to the invention in which R₆ is a cyano, ahalogeno or a C₁ -C₇ -alkylthio are then obtained by reactions known tothose skilled in the art.

The compounds (I) in which R₆ is an amino group substituted by a groupCH₂ R₃₆ are obtained by reacting a compound of the formula Hal-CH₂--COOR, in which Hal is a halogen, for example bromine, and R is a C₁-C₇ -alkyl or a benzyl, with a compound (I) in which R₆ is a group R₉NH--, in the presence of cuprous chloride; if appropriate, the resultingester is converted to the acid or an amide.

The compounds (I) in which R₆ is a guanidino group which isunsubstituted or monosubstituted or disubstituted by a (C₁ -C₇)alkyl, aphenyl or a benzyl can be prepared from compounds (I) in which R₆ is aphenoxycarboxamido group by reaction with cyanamide or a derivativethereof correctly substituted on the nitrogen.

The compounds of formula (I) in which R₆ is a (C₁ -C₇)alkoxycarbonyl canbe prepared directly by the method according to the invention. Bymethods known to those skilled in the art, they can be used to obtainthe compounds of formula (I) in which R₆ is a carboxyl group.

According to another procedure, the compounds of formula (I) in which R₆is a benzyloxycarbonyl can be used, by catalytic hydrogenation, toobtain the compounds (I) in which R₆ is a carboxyl. Reaction with athionyl halide gives the compounds of formula (I') in which R'₆ is ahalogenocarbonyl. Such compounds are reacted with a compound HNR₁₄ R₁₅in order to prepare compounds of formula (I) in which R₆ is a carbamoylsubstituted by R₁₄ and R₁₅.

The compounds of formula (I) in which R₆ is a phenoxycarbonyl can alsobe used to obtain the compounds of formula (I) in which R₆ is aphenylcarbamoyl or a (C₁ -C₇)alkylcarbamoyl by reaction with an anilineor a (C₁ -C₇)alkylamine. A substituted aniline or an alkylaminesubstituted on the alkyl makes it possible to obtain compounds offormula (I) in which R₆ is a phenylcarbamoyl substituted on the phenylor, respectively, an alkylcarbamoyl substituted on the alkyl.

The compounds of formula (I) in which R₆ is a carboxyl can also be usedto obtain the compounds of formula (I) in which R₆ is a group CONR₁₄ R₁₅by reaction with a compound of the formula HNR₁₄ R₁₅ in the presence ofBOP and an amine such as diisopropylethylamine.

The compounds of formula (I) in which R₆ is a group COR₁₂ can also beobtained by reacting a compound R₁₂ H with compounds (I) in which R₆ isa phenoxycarbonyl.

A compound of formula (I) in which R₆ is a thiocarbamoyl can be preparedby reacting Lawesson's reagent with a compound (I) in which R₆ is thecorresponding carbamoyl.

The compounds of formula (I) in which R₆ is a sulfamoyl substituted byR₁₆ and R₁₇ are obtained by reacting a compound HNR₁₆ R₁₇ with acompound of formula (I') in which R'₆ is a halogenosulfonyl group.

Methods known to those skilled in the art can be used to resolve theenantiomers of the compounds of formula (I) in which the carbon in the3-position of the indol-2-one is asymmetric. For example, the compoundsof formula (I) in which R₄ is an amino can be resolved using(S)-(+)-lactic acid, (S)-(+)-mandelic acid, (R)-(-)-mandelic acid,(R)-(+)-(naphth-1-yl)ethyl isocyanate, (R)-(-)-(naphth-1-yl)ethylisocyanate, (S)-(-)-α-methylbenzyl isocyanate, (R)-(+)-α-methylbenzylisocyanate, (1S)-(+)-10-camphorsulfonic acid or(1R)-(-)-10-camphorsulfonic acid.

It is also possible to carry out the optical resolution of the compoundsof formula (II). Thus the compounds of formula (II) in which R'₄ is anamino can be resolved according to the method described in Bull. Chem.Soc. Jpn., 1992, 65, 2359-2365, and illustrated below. Reaction of acompound of formula (V) with (S)-(+)-2-phenylglycinol or(R)-(-)-2-phenylglycinol gives a mixture of diastereoisomers of acompound of formula (II) in which R'₄ is NH--CH(C₆ H₅)--CH₂ OH, whichcan be separated for example by chromatography or crystallization. Then,oxidation of one of the above diastereoisomers with lead tetraacetateand hydrolysis in an acid medium gives an enantiomerically pure compoundof formula (II) in which R'₄ is an amino.

In the course of any one of the steps of the method of preparing thecompounds of formula (I) or their intermediates of formula (II), (III)or (IV), it may be necessary and/or desirable to protect the reactive orsensitive functional groups, such as the amine, hydroxyl, thiol orcarboxyl groups, present on any one of the molecules in question. Thisprotection can be effected using the conventional protective groups suchas those described in Protective Groups in Organic Chemistry, J. F. W.McOmie, published by Plenum Press, 1973, and in Protective Groups inOrganic Synthesis, T. W. Greene and P. G. M. Wutts, published by JohnWiley and Sons, 1991. The protective groups can be removed in asubsequent opportune step by using the methods known to those skilled inthe art which do not affect the rest of the molecule in question.

The affinity of the compounds according to the invention for thevasopressin receptors was determined in vitro using the method describedin C. J. Lynch et al., J. Biol. Chem., 1985, 260 (5), 2844-2851. Thismethod consists in studying the displacement of tritiated vasopressinbound to the V₁ sites of rat liver membranes. The concentrations of thecompounds according to the invention which cause a 50% inhibition of thebinding of tritiated vasopressin (IC₅₀) are low, ranging down to 10⁻⁹ M.

The affinity of the compounds (I) according to the invention for the V₂receptors was measured on a bovine kidney membrane preparation by amethod adapted from P. Crause et al., Molecular and CellularEndocrinology, 1982, 28, 529-541, and F. L. Stassen et al., J.Pharmacol. Exp. Ther., 1982, 223, 50-54. The compounds according to theinvention inhibit the binding of tritiated arginine vasopressin to thereceptors of the membrane preparation. The IC₅₀ values of the compoundsaccording to the invention are low, ranging down to 10⁻⁹ M.

The antagonistic activity of the compounds according to the inventiontowards the V₂ receptors was demonstrated by the adenylate cyclaseactivity assay performed by a method adapted from M. Laburthe et al.,Molecular Pharmacol., 1986, 29, 23-27. A bovine kidney membranepreparation is used and each product is incubated for 10 minutes at 37°C., either by itself or in the presence of AVP (arginine vasopressin) ata concentration of 3.10⁻⁸ M. The cyclic AMP (cyclic adenosinemonophosphate) produced is measured by radioimmunoassay. Theconcentration which causes a 50% inhibition (IC₅₀) of the stimulation ofadenylate cyclase induced by 3.10⁻⁸ M AVP is determined. The IC₅₀ valuesdetermined are of the order of 10⁻⁷ M, ranging down to 10⁻⁹ M.

The agonistic or antagonistic activity of the compounds according to theinvention, administered orally, towards the vasopressin receptors isevaluated in hyperhydrated rats (OFA, Sprague-Dawley strain) treatedwith vasopressin. The antagonistic activity of the compounds accordingto the invention was also evaluated in normally hydrated rats (OFA,Sprague-Dawley strain) by the technique described in Br. J. Pharmacol.,1992, 105, 787-791. The diuretic effect was observed for some compoundsat a dose of 10 mg/kg.

Likewise, the affinity of the compounds (I) according to the inventionfor the ocytocin receptors was determined in vitro by the displacementof a radioiodinated ocytocin analog bound to the receptors of agestating rat mammary gland membrane preparation by a technique similarto that described by J. Eland et al. in Eur. J. Pharmacol., 1987, 147,197-207. The IC₅₀ values of the compounds according to the inventionreach 10⁻⁹ M.

The compounds according to the invention are active after administrationby different routes, especially orally.

No signs of toxicity are observed with these compounds at thepharmacologically active doses.

Thus the compounds according to the invention can be used in thetreatment or prevention of various vasopressin-dependent orocytocin-dependent complaints, cardiovascular complaints such ashypertension, pulmonary hypertension, cardiac insufficiency, myocardialinfarction or coronary vasospasm, in particular in smokers, unstableangina and PTCA (percutaneous transluminal coronary angioplasty),cardiac ischemia, hemostatic disorders, especially hemophilia, and vonWillebrand's syndrome; complaints of the central nervous system, forexample migraine, cerebral vasospasm, cerebral hemorrhage, cerebraledemas, depression, anxiety, psychotic states and memory disorders;complaints of the renal system, such as edemas, renal vasospasm,necrosis of the renal cortex, hyponatremia, hypokalemia and SchwartzBartter's syndrome; complaints of the gastric system, such as gastricvasospasm, hepatocirrhosis, ulcers, the pathology of vomiting, forexample nausea, including nausea due to chemotherapy, travel sickness orelse the syndrome of inappropriate secretion of antidiuretic hormone(SIADH), diabetes insipidus and enuresis. The compounds according to theinvention can also be used in the treatment of disorders of sexualbehavior; in women, the compounds according to the invention can be usedfor treating dysmenorrhea or premature labor. The compounds according tothe invention can also be used in the treatment of small cell lungcancer, hyponatremic encephalopathy, Raynaud's disease, pulmonarysyndrome, glaucoma and cataract and in postoperative treatments,especially after abdominal surgery.

The present invention further relates to pharmaceutical compositionscontaining an effective dose of a compound according to the invention,or a pharmaceutically acceptable salt thereof, and suitable excipients.

Said excipients are chosen according to the pharmaceutical form and thedesired mode of administration.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical,intratracheal, intranasal, transdermal or rectal administration, theactive principles of formula (I) above, or their salts whereappropriate, can be administered to animals and humans in unit forms ofadministration, mixed with conventional pharmaceutical carriers, for theprophylaxis or treatment of the above disorders or diseases. Theappropriate unit forms of administration include forms for oraladministration, such as tablets, gelatin capsules, powders, granules andsolutions or suspensions to be taken orally, forms for sublingual,buccal, intratracheal or intranasal administration, aerosols, implants,forms for subcutaneous, intramuscular or intravenous administration andforms for rectal administration. For topical application, the compoundsaccording to the invention can be used in creams, ointments or lotions.

To obtain the desired prophylactic or therapeutic effect, the dose ofactive principle can vary between 0.01 and 50 mg per kg of body weightand per day.

Each unit dose can contain from 0.5 to 1000 mg, preferably from 1 to 500mg, of active ingredients in combination with a pharmaceutical carrier.This unit dose can be administered 1 to 5 times a day so as toadminister a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

If a solid composition in the form of tablets is prepared, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatin, starch, lactose, magnesium stearate, talc, silica or the like.The tablets can be coated with sucrose, a cellulose derivative or otherappropriate substances, or else they can be treated so as to have asustained or delayed activity and so as to release a predeterminedamount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with a diluent and incorporating the resulting mixtureinto soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops can contain the active ingredient together with asweetener, which is preferably calorie-free, methylparaben andpropylparaben as antiseptics, a flavoring and an appropriate dye.

The water-dispersible powders or granules can contain the activeingredient mixed with dispersants or wetting agents, or suspendingagents such as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

Parenteral administration is effected using aqueous suspensions,isotonic saline solutions or sterile and injectable solutions whichcontain pharmacologically compatible dispersants and/or wetting agents,for example propylene glycol or polyethylene glycol.

The active principle can also be formulated as microcapsules ormicrospheres, if appropriate with one or more carriers or additives.

In addition to the products of formula (I) above or one of theirpharmaceutically acceptable salts, the compositions of the presentinvention can contain other active principles which may be useful in thetreatment of the disorders or diseases indicated above.

Thus the present invention further relates to pharmaceuticalcompositions in which several active principles are present inassociation, one of them being a compound according to the invention.

Thus, according to the present invention, it is possible to preparepharmaceutical compositions in which a compound according to theinvention is present in association with a compound which acts on thereninangiotensin system, such as a converting enzyme inhibitor, anangiotensin II antagonist or a renin inhibitor. A compound according tothe invention can also be associated for example with a peripheralvasodilator, a calcium inhibitor, a beta-blocker, an alpha-1-blocker ora diuretic. Such compositions will be useful in particular in thetreatment of hypertension or heart failure.

It is also possible to associate two compounds according to theinvention, namely a specific V₁ receptor antagonist with a specific V₂receptor antagonist, or else a specific V₁ receptor antagonist with aspecific ocytocin antagonist.

These associations will make it possible to reinforce the therapeuticactivities of the compounds according to the invention.

The invention will now be described in greater detail by means of thenon-limiting illustrative Preparations and Examples below.

PREPARATIONS Preparations of the 1,3-dihydroindol-2-ones (II)Preparation 1 3-Amino-5-chloro-1,3-dihydro-3-phenylindol-2-one A)5-Chloro-1,3-dihydro-3-phenylindol-2-one

This compound is prepared according to Aeberli P. and Houlikan W. J. inJ. Org. Chem., 1968, 33 (4), 1640-1643.

B) 3-Bromo-5-chloro-1,3-dihydro-3-phenylindol-2-one

This compound is prepared according to Bolotov V. V. et al. in Farm. Zh.(Kiev), 1976, 5, 30-33.

A mixture of 3.0 g of the compound obtained in the previous step and 80ml of CCl₄ is heated to the reflux point and a solution of 2.5 g ofbromine in 3 ml of CCl₄ is added slowly. After refluxing for 30 minutes,the reaction mixture is cooled and evaporated under vacuum. The expectedproduct is used as such in the next step.

C) 3-Amino-5-chloro-1,3-dihydro-3-phenylindol-2-one

A solution of the compound obtained in the previous step in 30 ml ofether is cooled to 0° C. and a stream of gaseous ammonia is passedthrough. After stirring for 72 hours at RT, the mixture is evaporatedunder vacuum and the residue is taken up with water, extracted withAcOEt, washed with water, dried over sodium sulfate and evaporated undervacuum. The residue is chromatographed on silica using aDCM/AcOEt/hexane mixture (40/40/20; v/v/v) as the eluent to give theexpected product after crystallization from an AcOEt/MeOH mixture. m=1.4g. M.p.=230°-235° C.

Preparation 2 3-Amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) N-p-Chlorophenyl-DL-2-chloromandelamide

A mixture of 38.25 g of p-chloroaniline, 55.95 g of DL-2-chloromandelicacid and 280 ml of 1,2-dichlorobenzene is heated at 200° C. for 7 hours,the water formed being removed by means of a Dean-Stark apparatus. Thereaction mixture is partially concentrated under vacuum and left tocrystallize. The crystalline product formed is filtered off and washedwith iso ether to give 44.92 g of the expected product.

B) 5-Chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

172 ml of concentrated sulfuric acid (95%) are cooled to 10° C., 39 mlof fuming sulfuric acid (30% oleum) are added and 42.92 g of thecompound obtained in the previous step are then added in portions, theinternal temperature being kept below 40° C. The reaction mixture isstirred for 24 hours at RT and poured into iced water and theprecipitate formed is filtered off and washed with water. Theprecipitate is dissolved in chloroform, the organic phase is washed withwater to pH 7 and dried over sodium sulfate and the solvent isevaporated off under vacuum to give 35 g of the expected product aftercrystallization from a DCM/THF/iso ether mixture. M.p.=198°-200° C.

C) 3-Bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described in step Bof Preparation 1. This compound can also be prepared according to thefollowing procedure: A solution of 11.62 g of bromine in 15 ml ofchloroform is added slowly at RT to a solution of 22.44 g of thecompound obtained in the previous step in 500 ml of chloroform. Themixture is then evaporated under vacuum and the residue is taken up withDCM and evaporated under vacuum. The expected product is used as such.

D) 3-Amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described in step Cof Preparation 1 from the compound obtained in the previous step. Theexpected product is obtained after crystallization from a DCM/iso ethermixture. M.p.=234° C.

Preparation 35-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)indol-2-one

0.460 g of gaseous methylamine dissolved in 4 ml of ether is added at RTto a solution of 4.4 g of the compound obtained in step C of Preparation2 in 30 ml of DCM. After stirring for 30 minutes, the mixture isextracted with DCM, washed with water, dried over sodium sulfate andevaporated under vacuum. The residue is chromatographed on silica usingan AcOEt/hexane mixture (50/50; v/v) as the eluent to give the expectedproduct after crystallization from a DCM/iso ether mixture. m=0.655 g.M.p.=230° C.

The indol-2-one derivatives below are obtained by following the sameprocedure and varying the amine:

5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one,m.p.=148°-151° C.

5-Chloro-3-(2-chlorophenyl)-3-(diethylamino)-1,3-dihydroindol-2-one,m.p.=160°-165° C.

5-Chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydroindol-2-one,m.p.=240°-242° C.

5-Chloro-3-(2-chlorophenyl)-I,3-dihydro-3-(propylamino)indol-2-one,m.p.=218°-220° C.

3-(tert-Butylamino)-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one,m.p.=203°-204° C.

5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(isobutylamino)indol-2-one,m.p.=185° C.

5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(pentylamino)indol-2-one,m.p.=155° C.

3-(Benzylamino)-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one,m.p.=170°-175° C.

5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(2-meth-oxyethyl)amino!indol-2-one, m.p.=174°-176° C.

Preparation 4 Ethyl N-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-3-yl!glycinate

0.435 g of DIPEA is added slowly to a mixture of 0.500 g of the compoundobtained in step C of Preparation 2, 0.281 g of ethyl glycinatehydrochloride and 10 ml of chloroform. After stirring for 1 hour, themixture is washed with water, dried over sodium sulfate and evaporatedunder vacuum. The residue is chromatographed on silica using a DCM/AcOEtmixture (90/10; v/v) as the eluent to give the expected product aftercrystallization from a DCM/iso ether mixture. m=0.30 g. M.p.=175° C.

Preparation 53-(4-tert-Butoxycarbonylpiperazin-1-yl)-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 1 g of the compound obtained in step C of Preparation 2 in5 ml of chloroform is added at RT to a solution of 0.525 g of1-tert-butoxycarbonylpiperazine and 0.348 g of DIPEA in 20 ml ofchloroform. The mixture is stirred for 18 hours at RT and then washedwith water, dried over sodium sulfate and evaporated under vacuum. Theresidue is chromatographed on silica using an AcOEt/hexane mixture(20/80; v/v) as the eluent to give the expected product aftercrystallization from a DCM/iso ether mixture. m=0.54 g. M.p.=235° C.

Preparation 65-Chloro-1,3-dihydro-3-hydroxy-3-(2-methoxyphenyl)indol-2-one

A solution of 2-methoxyphenylmagnesium bromide is prepared from 1.35 gof magnesium and 10.5 g of 1-bromo-2-methoxybenzene in 100 ml of ether.This solution is added in 10 minutes at RT, under an argon atmosphere,to a mixture of 4.1 g of 5-chloroisatin and 70 ml of THF. After stirringfor 1 hour at RT, water is added and the product is filtered off,redissolved in THF, dried over magnesium sulfate and evaporated undervacuum in the presence of iso ether. The residue is chromatographed onsilica using a DCM/AcOEt mixture (60/40; v/v) as the eluent to give theexpected product after crystallization from a THF/iso ether mixture.m=3.7 g. M.p.=235°-238° C.

Preparation 73-Amino-5-chloro-1,3-dihydro-3-(2-methoxyphenyl)indol-2-one A)5-Chloro-1,3-dihydro-3-(2-methoxyphenyl)-3-(methylsulfonyloxy)indol-2-one

A solution of 0.500 g of the compound obtained in Preparation 6 in 7 mlof THF is cooled to -10° C. and 0.350 g of triethylamine and then 0.400g of methanesulfonyl chloride are added. This solution is kept for 48hours at a temperature of between 0 and +20° C. and used as such in thenext step.

B) 3-Amino-5-chloro-1,3-dihydro-3-(2-methoxyphenyl)-indol-2-one

The solution obtained in the previous step is cooled to 0° C. andgaseous ammonia is introduced by bubbling. The mixture is stirred for 24hours at RT and evaporated under vacuum. The residue is taken up with a5% solution of potassium carbonate, extracted with AcOEt, washed withwater, dried over sodium sulfate and evaporated under vacuum. Theresidue is chromatographed on silica using a DCM/AcOEt mixture (70/30;v/v) as the eluent to give the expected product after crystallizationfrom a DCM/MeOH mixture. m=0.182 g. M.p.=231°-233° C.

This compound can also be obtained by following the two steps of themethod described below.

A') 3,5-Dichloro-1,3-dihydro-3-(2-methoxyphenyl)indol-2-one

A mixture of 2.15 g of the compound obtained in Preparation 6 and 75 mlof DCM is cooled to 0° C. and 1.1 ml of pyridine and then 0.75 ml ofthionyl chloride are added. After stirring for two hours, the reactionmixture is chromatographed directly on silica using DCM and then aDCM/AcOEt mixture (80/20; v/v) as the eluent to give the expectedproduct after crystallization from a DCM/AcOEt mixture. m=1.9 g.M.p.=220°-224° C.

B') 3-Amino-5-chloro-1,3-dihydro-3-(2-methoxyphenyl)-indol-2-one

10 ml of a solution of ammonia in THF (1.16 g of gaseous ammonia in 110ml of THF) are added at RT to a solution of 1.9 g of the compoundobtained in the previous step in 80 ml of THF. After stirring for 2hours at RT, a further 10 ml of the solution of ammonia in THF are addedand the mixture is stirred for 30 hours. The solvent is evaporated offunder vacuum and the residue is taken up with a 5% solution of potassiumcarbonate and extracted with AcOEt. An insoluble material, which is theexpected product, is filtered off and recrystallized from a THF/MeOHmixture. M.p.=231°-232° C. To obtain a second crop, the organic phase istaken up with AcOEt, washed with water, dried over sodium sulfate andevaporated under vacuum. The residue is chromatographed on silica usinga DCM/AcOEt mixture (50/50; v/v) as the eluent to give a total of 0.88 gof the expected product.

Preparation 8 3-Azido-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 3.00 g of the compound obtained in step C of Preparation 2,1.65 g of sodium azide and 100 ml of acetonitrile is refluxed for 1hour. After evaporation under vacuum, the residue is taken up withwater, extracted with AcOEt, washed with water and with a saturatedsolution of NaCl, dried over sodium sulfate and evaporated under vacuumto give the expected product after crystallization from a DCM/isoether/THF mixture. m=0.894 g. M.p.=178° C.

Preparations 9 and 103-Amino-5,6-dichloro-1,3-dihydro-3-phenylindol-2-one (Preparation 9) and3-amino-4,5-dichloro-1,3-dihydro-3-phenylindol-2-one (Preparation 10) A)5,6-Dichloro-1,3-dihydro-3-phenylindol-2-one and4,5-dichloro-1,3-dihydro-3-phenylindol-2-one

A mixture of these two compounds is prepared according to the proceduredescribed in step B of Preparation 2 fromN-3,4-dichlorophenyl-DL-mandelamide, itself obtained according to theprocedure described in step A of Preparation 2 from 3,4-dichloroanilineand DL-mandelic acid. The mixture of the two expected products isobtained after recrystallization from EtOH.

B) 3-Bromo-5,6-dichloro-1,3-dihydro-3-phenylindol-2-one and3-bromo-4,5-dichloro-1,3-dihydro-3-phenylindol-2-one

A solution of 2.6 g of bromine in 2 ml of chloroform is added in 5minutes at RT to a suspension of 4.71 g of the mixture of the twocompounds obtained in the previous step in 70 ml of chloroform. Stirringfor 30 minutes and evaporation under vacuum gives the mixture of the twoexpected products, which is used as such in the next step.

C) 3-Amino-5,6-dichloro-1,3-dihydro-3-phenylindol-2-one (Preparation 9)and 3-amino-4,5-dichloro-1,3-dihydro-3-phenylindol-2-one (Preparation10)

A solution of the mixture of the two compounds obtained in the previousstep in 20 ml of THF is cooled to 0° C. and a solution of 0.60 g ofgaseous ammonia in 10 ml of THF is added. After stirring for two hours,a further solution of 0.30 g of gaseous ammonia in 5 ml of THF is addedand the mixture is stirred for 48 hours, the temperature being allowedto rise to RT. The reaction medium is evaporated under vacuum, extractedwith AcOEt, washed with water, dried over sodium sulfate and evaporatedunder vacuum. The residue is chromatographed on silica using a DCM/AcOEtmixture (75/25; v/v) as the eluent to give the product of Preparation 9after crystallization from a DCM/AcOEt mixture. Elution is then carriedout with a DCM/AcOEt mixture (40/60; v/v) to give the product ofPreparation 10 after crystallization from a DCM/iso ether mixture.

Compound of Preparation 9, m.p.=211°-212° C.

Compound of Preparation 10, m.p.=185°-187° C.

Preparation 115-Ethoxy-3-(2-ethoxycarbonyl-1-ethoxycarbonylhydrazino)-1,3-dihydro-3-phenylindol-2-oneA) 5-Ethoxy-1,3-dihydro-3-phenylindol-2-one

This compound is prepared according to the procedure described in step Bof Preparation 66 from N-4-ethoxyphenyl-DL-mandelamide (138° C.), itselfobtained according to the procedure described in step A of Preparation 2from 4-ethoxyaniline and DL-mandelic acid. This gives the expectedproduct. M.p.=125°-130° C.

B)5-Ethoxy-3-(2-ethoxycarbonyl-1-ethoxycarbonylhydrazino)-1,3-dihydro-3-phenylindol-2-one

A mixture of 3.42 g of the compound obtained in the previous step and 30ml of THF is cooled to -70° C. and 20 ml of a 1.5M solution of lithiumdiisopropylamide in cyclohexane are added slowly under an argonatmosphere. The mixture is stirred for 15 minutes, the temperature beingallowed to rise to -20° C., it is then cooled to -70° C. and 2.38 g ofdiethyl azodicarboxylate are added all at once. After stirring for 30minutes, water is added, the temperature is allowed to rise to RT andthe solvent is evaporated off under vacuum. The residue is extractedwith AcOEt, washed with water and with a saturated solution of NaCl,dried over sodium sulfate and evaporated under vacuum. The residue ischromatographed on silica using a DCM/AcOEt mixture (65/35; v/v) as theeluent to give the expected product after crystallization from a DCM/isoether mixture. m=2.7 g. M.p.=202°-204° C.

Preparations 12 and 13 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(1S)-1-(methoxycarbonyl)ethyl!amino!indol-2-one, isomer A and isomer B

2.04 g of DIPEA are added to a mixture of 2.00 g of the compoundobtained in step C of Preparation 2, 1.12 g of methyl (L)-alaninatehydrochloride and 40 ml of chloroform. After stirring for 18 hours, themixture is washed with water, dried over sodium sulfate and evaporatedunder vacuum. The residue is chromatographed on silica using anAcOEt/hexane mixture (40/60; v/v) as the eluent. The two isomers areseparated out:

the less polar isomer, A: compound of Preparation 12. m=0.639 g.M.p.=214° C. α_(D) ²⁰ =+137.2° (c=0.53; chloroform);

the more polar isomer, B: compound of Preparation 13. m=0.400 g.M.p.=165° C. α_(D) ²⁰ =155.2° (c=0.38; chloroform).

Preparation 145-Chloro-1,3-dihydro-3-hydroxy-3-(2-methylphenyl)indol-2-one

A solution of 2-methylphenylmagnesium bromide is prepared from 2.7 g ofmagnesium, 19 g of 1-bromo-2-methylbenzene and 100 ml of ether. Amixture of 5.04 g of 5-chloroisatin and 100 ml of THF is cooled in anice bath under an argon atmosphere and the solution of magnesiumcompound prepared above is added slowly. After stirring for 4 hours,water is added and the solvents are evaporated off under vacuum. Theresidue is extracted with AcOEt, the precipitate formed is filtered offand the organic phase of the filtrate is dried over magnesium sulfateand evaporated under vacuum. The residue obtained, combined with theprecipitate previously filtered off, is crystallized from MeOH to give4.8 g of the expected product. M.p.=285°-295° C.

Preparation 153-Amino-5-chloro-1,3-dihydro-3-(2-methylphenyl)indol-2-one A)3,5-Dichloro-1,3-dihydro-3-(2-methylphenyl)indol-2-one

A mixture of 2 g of the compound obtained in Preparation 14 and 72 ml ofDCM is cooled to 0° C. and 1.04 ml of pyridine and then 0.76 ml ofthionyl chloride are added. After stirring for 15 minutes, the reactionmixture is chromatographed directly on silica using a gradient of aDCM/AcOEt mixture (from 95/5; v/v to 80/20; v/v) as the eluent to givethe expected product, which is used as such in the next step.

B) 3-Amino-5-chloro-1,3-dihydro-3-(2-methylphenyl)-indol-2-one

A solution of 1.97 g of the compound obtained in the previous step in 80ml of THF is cooled to 0° C. and a solution of 0.230 g of gaseousammonia in 20 ml of THF is added. After stirring for 24 hours at RT,water is added, the solvent is evaporated off and the residue isextracted with AcOEt, washed with water, dried over sodium sulfate andevaporated under vacuum. The residue is chromatographed on silica usinga gradient of a DCM/AcOEt mixture (from 80/20; v/v to 60/40; v/v) as theeluent to give the expected product after crystallization from anMeOH/iso ether mixture. m=1.10 g. M.p.=218°-222° C.

Preparation 163-Amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one A)3-(2-Chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described in step Bof Preparation 66 from N-4-ethoxyphenyl-DL-2-chloromandelamide(120°-130° C.), itself obtained according to the procedure described instep A of Preparation 2 from 4-ethoxyaniline and DL-2-chloromandelicacid. This gives the expected product. M.p.=176°-180° C.

B) 3-Chloro-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one

1.16 g of N-chlorosuccinimide are added to a suspension of 2.5 g of thecompound obtained in the previous step in 100 ml of CC₄ and the mixtureis refluxed for 1 hour. After cooling to RT, the insoluble material isfiltered off and the filtrate is evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5;v/v) as the eluent to give the expected product after recrystallizationfrom a DCM/hexane mixture. m=1.46 g. M.p.=128°-132° C.

This compound can also be obtained by following the two steps of themethod described below.

A') 3-(2-Chlorophenyl)-5-ethoxy-1,3-dihydro-3-hydroxyindol-2-one

This compound is prepared according to the procedure described inPreparation 6 from 5-ethoxyisatin and 2-chlorophenylmagnesium bromide(prepared according to P. G. Gassman in J. Am. Chem. Soc., 1974, 9,5512).

B') 3-Chloro-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described in stepAl of Preparation 7 from the compound obtained in the previous step andthionyl chloride. M.p.=128°-132° C.

C) 3-Azido-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one

0.339 g of sodium azide is added to a solution of 0.560 g of thecompound obtained in step B or B' in 20 ml of acetonitrile and themixture is refluxed for 30 minutes. The solvent is evaporated off undervacuum and the residue is taken up with water, extracted with AcOEt,washed with a saturated solution of NaCl, with water and with a 5%aqueous solution of sodium dithionite, re-extracted with DCM, dried oversodium sulfate and evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5;v/v) as the eluent to give 0.377 g of the expected product. Infraredspectrum in DCM: 3440 cm⁻¹, 2100 cm⁻¹, 1745 cm⁻¹.

D) 3-Amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one

0.83 ml of triethylamine and then 0.60 ml of propane-1,3-dithiol areadded by syringe, under an argon atmosphere, to a solution of 0.975 g ofthe compound obtained in the previous step in 14.8 ml of MeOH and thereaction mixture is heated at 60° C. overnight. It is evaporated undervacuum and the residue is chromatographed directly on silica using DCMand then a DCM/AcOEt mixture (70/30; v/v) as the eluent to give 0.786 gof the expected product, a sample of which is recrystallized from aDCM/iso ether mixture. M.p.=173°-175° C.

Preparation 17 5-Chloro-3-cyclohexyl-1,3-dihydro-3-hydroxyindol-2-one

A suspension of 18.15 g of 5-chloroisatin in 45 ml of THF is cooled to+4° C., 200 ml of a 2M solution of cyclohexylmagnesium chloride in etherare added dropwise and the mixture is stirred for 3 hours at RT. 900 mlof a saturated solution of ammonium chloride are added and the solventsare concentrated under vacuum. The aqueous phase is extracted withAcOEt, the organic phase is washed with a saturated solution of NaCl anddried over sodium sulfate and the solvent is evaporated of f undervacuum to give 4 g of the expected product after crystallization from aTHF/AcOEt mixture.

NMR spectrum at 200 MHz in DMSO-d₆

0.4 to 2.0 ppm: m: 11H

5.9 ppm: s: 1H

6.8 ppm: d: 1H

7.2 ppm: m: 2H

10.35 ppm: s: 1H

Preparation 185-Chloro-3-cyclohexyl-1,3-dihydro-3-(methylamino)indol-2-one A)3,5-Dichloro-3-cyclohexyl-1,3-dihydroindol-2-one

A solution of 1 g of the compound obtained in Preparation 17 in 40 ml ofDCM is cooled to +4° C. and 0.57 ml of pyridine and then 0.42 ml ofthionyl chloride are added. After stirring for 10 minutes, the reactionmixture is chromatographed directly on silica using DCM and then aDCM/AcOEt mixture (95/5; v/v) as the eluent to give 1 g of the expectedproduct, which is used as such in the next step.

B) 5-Chloro-3-cyclohexyl-1,3-dihydro-3-(methylamino)-indol-2-one

0.88 ml of a 33% solution of methylamine in EtOH is added at RT to asolution of 1 g of the compound obtained in the previous step in 15 mlof THF and the mixture is stirred for 24 hours. Water is added to thereaction mixture, the solvent is concentrated under vacuum, the aqueousphase is extracted with AcOEt, the organic phase is washed with asaturated solution of NaCl and dried over sodium sulfate and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/AcOEt mixture (80/20; v/v) as the eluent togive 0.85 g of the expected product after crystallization from a DCM/isoether mixture. M.p.=195°-198° C.

Preparation 195-Chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-hydroxyindol-2-one

A solution of cyclohexylmethylmagnesium bromide is prepared from 5.37 gof magnesium and 30.8 ml of bromomethylcyclohexane in 15 ml of ether.This solution is added dropwise at +4° C., under an argon atmosphere, toa mixture of 10 g of 5-chloroisatin and 25 ml of THF. After stirring for3 hours at RT, 500 ml of a saturated solution of ammonium chloride areadded, extraction is carried out with AcOEt, the organic phase is washedwith a saturated solution of NaCl and with water and dried over sodiumsulfate and the solvent is evaporated off under vacuum to give 12 g ofthe expected product after crystallization from AcOEt andrecrystallization from a THF/AcOEt mixture. M.p.=252°-253° C. (dec.).

This compound can also be obtained by following the three steps of themethod described below.

A') 5-Chloro-3-(cyclohexylmethylene)-1,3-dihydroindol-2-one

A solution of 10 g of 5-chloro-1,3-dihydroindol-2-one, 6.18 g ofcyclohexanecarboxaldehyde and 4.93 ml of pyrrolidine in 250 ml oftoluene is refluxed for 1 hour, the water formed being removed by meansof a Dean-Stark apparatus. The reaction mixture is concentrated to about90 ml and left to crystallize. The crystalline product formed isfiltered off and washed with toluene and then with iso ether to give 9.7g of the expected product after recrystallization from toluene.M.p.=203°-204° C.

B') 5-Chloro-3-(cyclohexylmethyl)-1,3-dihydroindol-2-one

1.08 g of sodium borohydride are added in portions to a mixture of 7.5 gof the compound obtained in the previous step, 60 ml of MeOH and 60 mlof THF and the reaction mixture is stirred for 30 minutes at RT. Thesolvent is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with a saturated solution of NaCl andwith water and dried over sodium sulfate and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica using DCM andthen a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 3.76 g ofthe expected product after crystallization from a DCM/iso ether mixture.M.p.=152°-153° C.

C') 5-Chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-hydroxyindol-2-one

0.083 g of sodium hydride as a 60% dispersion in oil is added to asolution of 0.5 g of the compound obtained in the previous step in 30 mlof THF and the mixture is stirred for 10 minutes at RT. 0.22 ml ofdimethyl disulfide is then introduced and the mixture is stirred for 1hour at RT. 200 ml of water are added to the reaction mixture and theprecipitate formed is filtered off and washed with water and then withiso ether to give 0.45 g of the expected product.

Preparation 205-Chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-(methylamino)indol-2-one A)3,5-Dichloro-3-(cyclohexylmethyl)-1,3-dihydroindol-2-one

A solution of 1 g of the compound obtained in Preparation 19 in 5 ml ofDCM is cooled to +4° C. and 0.56 ml of pyridine and then 0.4 ml ofthionyl chloride are added. After stirring for 3 hours, the reactionmixture is chromatographed directly on silica using DCM and then aDCM/AcOEt mixture (95/5; v/v) as the eluent to give 1.1 g of theexpected product, which is used as such in the next step.

B) 5-Chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-(methylamino)indol-2-one

0.33 ml of an 8.03M solution of methylamine in EtOH is added at RT to asolution of 0.4 g of the compound obtained in the previous step in 10 mlof DCM and the mixture is stirred for 3 hours at RT. It is concentratedunder vacuum, the residue is taken up with a 5% solution of sodiumhydrogencarbonate, extracted with AcOEt, washed with a saturatedsolution of NaCl and with water and dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using DCM and then a DCM/AcOEt mixture (60/40; v/v) as theeluent to give 0.225 g of the expected product after crystallizationfrom a DCM/iso ether mixture. M.p.=168°-169° C.

Preparation 21 5-Chloro-3-(2-cyanoethyl)amino!-3-(cyclohexylmethyl)-1,3-dihydroindol-2-one

1.33 ml of triethylamine and then 0.412 g of 3-aminopropionitrilefumarate are added at RT to a solution of 0.960 g of the compoundobtained in step A of Preparation 20 in 5 ml of DCM and the reactionmixture is heated at 50° C. for 18 hours. It is concentrated undervacuum, the residue is taken up with a 5% solution of sodium carbonate,extracted with AcOEt, washed with a saturated solution of NaCl and withwater and dried over sodium sulfate and the solvent is evaporated offunder vacuum to give 0.5 g of the expected product after crystallizationfrom AcOEt. M.p.=208°-209° C.

Preparation 22 3-Benzyl-5-chloro-1,3-dihydro-3-hydroxyindol-2-one

A suspension of 10 g of 5-chloroisatin in 150 ml of THF is cooled to +4°C., 220 ml of a 1M solution of benzylmagnesium chloride in ether areadded dropwise and the mixture is stirred for 3 hours at RT. 500 ml of asaturated solution of ammonium chloride are added and the solvents areconcentrated under vacuum. The aqueous phase is extracted with AcOEt,the organic phase is washed with a saturated solution of NaCl and withwater and dried over sodium sulfate and the solvent is evaporated offunder vacuum to give 5.6 g of the expected product after crystallizationfrom a THF/AcOEt mixture. M.p.=204°-205° C.

Preparation 23 3-Benzyl-5-chloro-1,3-dihydro-3-(methylamino)-indol-2-oneA) 3-Benzyl-3,5-dichloro-1,3-dihydroindol-2-one

A suspension of 4.63 g of the compound obtained in Preparation 22 in 25ml of THF is cooled to +4° C. and 2.8 ml of pyridine and then 2 ml ofthionyl chloride are added. After stirring for 3 hours at +4° C., thereaction mixture is concentrated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (97/3;v/v) as the eluent to give 1.2 g of the expected product, which is usedas such in the next step.

B) 3-Benzyl-5-chloro-1,3-dihydro-3-(methylamino)indol2-one

1.02 ml of an 8.03M solution of methylamine in EtOH are added at RT to asolution of 1.2 g of the compound obtained in the previous step in 3 mlof DCM and the mixture is stirred for 6 hours at RT. 50 ml of water areadded to the reaction mixture, extraction is carried out with AcOEt, theorganic phase is washed with a saturated solution of NaCl and with waterand dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using DCM and then aDCM/AcOEt mixture (60/40; v/v) as the eluent to give 0.8 g of theexpected product after crystallization from a DCM/iso ether mixture.M.p.=196° C.

Preparations 24 and 25 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(1S)-2-hydroxy-1-phenylethyl!amino!indol-2-one, isomer A and isomer B

A mixture of 5 g of the compound obtained in step C of Preparation 2,3.83 g of (S)-(+)-2-phenylglycinol and 100 ml of chloroform is stirredfor 3 days at RT. The reaction mixture is poured into a saturatedsolution of potassium carbonate and extracted with AcOEt and theinsoluble compound at the interphase (isomer B: compound of Preparation25) is filtered off. After decantation of the filtrate, the organicphase is washed 4 times with water and dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using a DCM/AcOEt mixture (80/20; v/v) as the eluent. Oneisomer is separated out:

the less polar isomer, A: compound of Preparation 24. m=2.3 g.M.p.=170°-172° C. after crystallization from a DCM/iso ether mixture.α_(D) ²⁵ =+263°(c=0.38; chloroform). Elution with a DCM/MeOH mixture(50/50; v/v) gives the other isomer:

the more polar isomer, B: compound of Preparation 25. m=1.64 g(insoluble material and chromatography). M.p.=294° C. afterrecrystallization from an MeOH/THF mixture. α_(D) ²⁵ =-31.8°(c=0.21;DMF).

Preparations 26 and 27 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(1R)-2-hydroxy-1-phenylethyl!amino!indol-2-one, isomer A and isomer B

A mixture of 5 g of the compound obtained in step C of Preparation 2,3.83 g of (R)-(-)-2-phenylglycinol and 200 ml of chloroform is stirredfor 12 hours at RT. The insoluble compound (isomer B: compound ofPreparation 27) is filtered off. The filtrate is concentrated undervacuum and the residue is chromatographed on silica using a gradient ofa DCM/AcOEt mixture (from 80/20; v/v to 70/30; v/v) as the eluent. Thetwo isomers are separated out:

the less polar isomer, A: compound of Preparation 26. m=2.43 g.M.p.=168° C. after crystallization from a DCM/iso ether mixture. α_(D)²⁵ =-268° (c=0.28; chloroform);

the more polar isomer, B: compound of Preparation 27. The insolublecompound obtained above is suspended in 500 ml of AcOEt and washed 6times with a 5% solution of sodium carbonate. The insoluble compound isfiltered off again, combined with the more polar compound obtained afterchromatography and recrystallized from an MeOH/THF mixture. m=1.49 g.M.p.=293°-298° C. α_(D) ²⁵ =+39.4°(c=0.2; DMF).

Preparation 283-Amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one, (+) isomer

A solution of 2.12 g of the compound obtained in Preparation 24 (isomerA) in 40 ml of DCM and 20 ml of MeOH is cooled in an ice bath, 2.48 g oflead tetraacetate are added and the reaction mixture is stirred for 40minutes at 0° C. A saturated solution of sodium hydrogencarbonate isadded to the reaction mixture, the organic solvents are concentratedunder vacuum, the aqueous phase is extracted with AcOEt, the organicphase is washed with water and dried over sodium sulfate and the solventis evaporated off under vacuum. The residue is taken up with 80 ml of a5N solution of HCl, 10 ml of ether are added and the mixture is stirredfor 10 minutes at RT. After decantation, the aqueous phase is washedtwice with ether, rendered alkaline by the addition of a 5% solution ofpotassium carbonate and extracted with AcOEt, the organic phase iswashed with water and with a saturated solution of NaCl and dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using a DCM/AcOEt mixture (70/30;v/v) as the eluent to give 1.25 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=174°-176° C. α_(D) ²⁵=+118°(c=0.47; chloroform).

Preparation 293-Amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one, (-) isomer

This compound is prepared according to the procedure described inPreparation 28 from 2.3 g of the compound obtained in Preparation 26(isomer A) and 2.72 g of lead tetraacetate in 40 ml of DCM and 20 ml ofMeOH. Chromatography on silica using a DCM/AcOEt mixture (75/25; v/v) asthe eluent gives 0.76 g of the expected product after crystallizationfrom a DCM/iso ether mixture. M.p.=175°-176° C. α_(D) ²⁵ =-121°(c=0.26;chloroform).

Preparation 305-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(isopentylamino)indol-2-one

A mixture of 1 g of the compound obtained in step C of Preparation 2,0.468 g of isopentylamine and 20 ml of chloroform is stirred for 1 hourat RT. The reaction mixture is washed with a 5% solution of sodiumcarbonate; then, after decantation, the organic phase is dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using a DCM/AcOEt mixture (95/5;v/v) as the eluent to give 0.78 g of the expected product aftercrystallization from a DCM/iso ether/hexane mixture. M.p.=152° C.

Preparation 31 5-Chloro-3-(2-chlorophenyl)-3-(1-ethoxycarbonylpiperid-4-yl)amino!-1,3-dihydroindol-2-one

A mixture of 5 g of the compound obtained in step C of Preparation 2,2.55 g of ethyl 4-aminopiperidine-1-carboxylate, 1.91 g of DIPEA and 100ml of chloroform is stirred for 2 hours at RT. The reaction mixture iswashed with water; then, after decantation, the organic phase is driedover sodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using a DCM/AcOEt mixture (90/10;v/v) as the eluent to give 5 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=204° C.

Preparation 32 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(3-methoxyphenyl)ethyl!amino!indol-2-one

1.63 ml of 3-methoxyphenethylamine are added at RT to a solution of 2 gof the compound obtained in step C of Preparation 2 in 40 ml of DCM andthe reaction mixture is stirred for 1 hour. It is washed with a 5%solution of potassium carbonate; then, after decantation, it is driedover sodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using DCM and then a DCM/AcOEtmixture (95/5; v/v) as the eluent to give 2 g of the expected productafter crystallization from a DCM/iso ether mixture. M.p.=155°-160° C.

Preparation 33 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(pyrid-2-yl)ethyl!amino!indol-2-one

A mixture of 5 g of the compound obtained in step C of Preparation 2,3.56 g of 2-(2-aminoethyl)-pyridine and 50 ml of chloroform is stirredfor 2 hours at RT. The reaction mixture is washed with water; then,after decantation, the organic phase is dried over sodium sulfate andthe solvent is evaporated off under vacuum. The residue ischromatographed on alumina using a DCM/AcOEt mixture (50/50; v/v) as theeluent to give 3.3 g of the expected product after crystallization froma DCM/iso ether mixture. M.p.=178° C.

Preparation 34 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(2-hydroxyethyl)amino!indol-2-one

A solution of 1.03 g of 2-aminoethanol and 3.45 g of triethylamine in 10ml of chloroform is added at RT to a suspension of 6 g of the compoundobtained in step C of Preparation 2 in 20 ml of chloroform and thereaction mixture is stirred for 3 hours at RT. It is partiallyconcentrated under vacuum and the precipitate formed is filtered off togive 4 g of the expected product after crystallization from a THF/AcOEtmixture. M.p.=198°-200° C.

Preparation 35 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(trimethylsilyloxy)ethyl!amino!indol-2-one

A mixture of 1.5 g of the compound obtained in Preparation 34, 0.72 g ofhexamethyldisilane, 0.03 g of zinc chloride and 15 ml of acetonitrile isheated at 60° C. for 4 hours. The reaction mixture is concentrated undervacuum, the residue is extracted with AcOEt, the organic phase is washedtwice with water and with a saturated solution of NaCl and dried oversodium sulfate and the solvent is evaporated off under vacuum to give1.084 g of the expected product after trituration in iso ether followedby filtration. Said product is used as such in EXAMPLE 114.

Preparation 36 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3- 2-2-(dimethylamino)ethoxy!ethyl!amino!indol-2-one A) 2-2-(tert-Butoxycarbonylamino)ethoxy!ethanol

21.8 g of di-tert-butyl dicarbonate are added in portions at RT to asolution of 10.5 g of 2-(2-aminoethoxy)ethanol in 50 ml of 1,4-dioxaneand the reaction mixture is stirred for 2 hours at RT. It is poured intowater and extracted three times with AcOEt, the organic phase is washedtwice with 20 ml of water and dried over sodium sulfate and the solventis evaporated off under vacuum to give 18.5 g of the expected product inthe form of an oil, which is used as such in the next step.

B) 2- 2-(tert-Butoxycarbonylamino)ethoxy!ethyl methanesulfonate

A solution of 18.5 g of the compound obtained in the previous step and9.2 g of triethylamine in 100 ml of DCM is cooled to 0° C. and asolution of 10.4 g of methanesulfonyl chloride in 15 ml of DCM is addeddropwise, the temperature being kept below 10° C. After stirring for twodays at RT, the reaction mixture is concentrated under vacuum, theresidue is taken up with AcOEt, the organic phase is washed with waterand with a saturated solution of NaCl and dried over sodium sulfate andthe solvent is evaporated off under vacuum to give 24.3 g of theexpected product in the form of an oil, which is used as such in thenext step.

C) N,N-Dimethyl-2- 2-(tert-butoxycarbonylamino)ethoxy!-ethylamine

A solution of 8.0 g of the compound obtained in the previous step in 100ml of ether is cooled to 0° C. and 7.5 g of a 33% solution ofdimethylamine in EtOH, diluted in 10 ml of ether, are added dropwise.The reaction mixture is stirred for 4 days at RT and concentrated undervacuum. The residue is taken up with a 1N solution of HCl, the acidaqueous phase is washed with ether, rendered alkaline by the addition ofpotassium carbonate and extracted 3 times with ether and once withAcOEt, the combined organic phases are dried over sodium sulfate and thesolvents are evaporated off under vacuum to give 1.15 g of the expectedproduct in the form of an oil, which is used as such in the next step.

D) 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3- 2-2-(dimethylamino)ethoxy!ethyl!amino!indol-2-one

A mixture of 1.15 g of the compound obtained in the previous step and 10ml of TFA is stirred for 90 minutes at 0° C. and concentrated undervacuum. The residue is dissolved in a solution of 2 g of triethylaminein 30 ml of chloroform and this solution is added dropwise at RT to asolution of 1.76 g of the compound obtained in step C of Preparation 2in 30 ml of chloroform. The reaction mixture is stirred for 3 hours andconcentrated under vacuum. The residue is taken up with a 5% solution ofpotassium carbonate and extracted 3 times with AcOEt, the organic phaseis washed with water and with a saturated solution of NaCl and driedover sodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on alumina using a DCM/MeOH mixture (98/2;v/v) as the eluent to give 1.15 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=165°-168° C.

Preparation 37 3- 2-2-(tert-Butoxycarbonylamino)ethoxy!-ethyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) 2- 2-(tert-Butoxycarbonylamino)ethoxy!ethyl azide

A mixture of 12.4 g of the compound obtained in step B of Preparation36, 2.9 g of sodium azide and 50 ml of DMSO is stirred for 18 hours atRT and then heated at 80° C. for 4 hours. The reaction mixture is pouredinto water and extracted with AcOEt, the organic phase is dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using a hexane/AcOEt mixture(70/30; v/v) as the eluent to give 7.4 g of the expected product in theform of an oil, which is used as such in the next step.

B) 2- 2-(tert-Butoxycarbonylamino)ethoxy!ethylamine

A mixture of 7.4 g of the compound obtained in the previous step, 1.5 gof Raney® nickel, 1.5 ml of hydrazine monohydrate and 60 ml of EtOH isstirred for 4 hours at RT. A further 1.5 ml of hydrazine monohydrate areadded and the mixture is stirred for 2 hours at RT. The catalyst isfiltered off and washed with EtOH and the filtrate is concentrated undervacuum to give 6.22 g of the expected product, which is used as such inthe next step.

C) 3- 2-2-(tert-Butoxycarbonylamino)ethoxy!ethyl!-amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 6.22 g of the compound obtained in the previous step and 2g of triethylamine in 30 ml of chloroform is added in 2 hours at RT to asuspension of 7.0 g of the compound prepared in step C of Preparation 2in 40 ml of chloroform and the reaction mixture is stirred for 3 hoursat RT. It is concentrated under vacuum, the residue is taken up with a5% solution of potassium carbonate and extracted with AcOEt, the organicphase is washed with water and with a saturated solution of NaCl anddried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a DCM/AcOEtmixture (50/50; v/v) as the eluent to give 7.3 g of the expected productafter crystallization from a DCM/iso ether mixture. M.p.=138°-140° C.

Preparation 38 5-Chloro-3-(2-chlorophenyl)-3-2-(diethylamino)ethyl!amino!-1,3-dihydroindol-2-one

A solution of 1.13 ml of N,N-diethylethylenediamine and 5.82 ml oftriethylamine in 20 ml of DCM is added dropwise at RT to a suspension of5 g of the compound obtained in step C of Preparation 2 in 30 ml of DCMand the reaction mixture is stirred for 3 hours at RT. It isconcentrated under vacuum, the residue is taken up with a 5% solution ofsodium carbonate and extracted with AcOEt, the organic phase is washedwith a saturated solution of NaCl and with water and dried over sodiumsulfate and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using DCM and then a DCM/MeOH mixture (70/30;v/v) as the eluent to give 2.21 g of the expected product.

NMR spectrum at 200 MHz in DMSO-d₆

0.8 ppm: t: 6H

2.0 to 2.6 ppm: m: 8H

2.8 ppm: mt: 1H

6.5 to 8.2 ppm: m: 7H

10.75 ppm: s: 1H

Preparation 39 5-Chloro-3-(2-chlorophenyl)-3- N-2-(diethylamino)ethyl!-N-methylamino!-1,3-dihydroindol-2-one

A mixture of 5 g of the compound obtained in step C of Preparation 2,3.8 g of N,N-diethyl-N'-methylethylenediamine and 100 ml of chloroformis stirred for 18 hours at RT. The reaction mixture is washed withwater, the organic phase is dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on aluminausing a DCM/MeOH mixture (97/3; v/v) as the eluent to give 3.6 g of theexpected product after crystallization from iso ether. M.p.=140° C.

Preparation 40 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(diisopropylamino)ethyl!amino!indol-2-one

A mixture of 5 g of the compound obtained in step C of Preparation 2,4.3 g of N,N-diisopropyl-ethylenediamine and 50 ml of chloroform isstirred for 18 hours at RT. The reaction mixture is washed with water,the organic phase is dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is taken up with iso ether and,after trituration, the solid formed is filtered off to give 4.2 g of theexpected product, which is used as such in EXAMPLE 159.

Preparation 41 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3- N-methyl-N-3-(dimethylamino)propyl!amino!indol-2-one

A mixture of 3.57 g of the compound obtained in step C of Preparation 2,1.16 g of N,N-dimethyl-N'-methylpropane-1,3-diamine, 1.01 g oftriethylamine and 40 ml of chloroform is stirred overnight at RT. Afterconcentration under vacuum, the residue is taken up with a 5% solutionof sodium carbonate and extracted with AcOEt, the organic phase iswashed with water and with a saturated solution of NaCl and dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on alumina using a DCM/MeOH mixture (98/2;v/v) as the eluent to give 2.36 g of the expected product, which is usedas such in EXAMPLE 161.

Preparation 42 3-4-(tert-Butoxycarbonylamino)butyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) 3-(4-Aminobutyl)aminol!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 5 g of the compound obtained in step C of Preparation 2 in50 ml of chloroform and 15 ml of THF is added dropwise at RT to asolution of 5.6 ml of 1,4-diaminobutane in 10 ml of chloroform. Thereaction mixture is stirred for 3 hours at RT and partially concentratedand the precipitate formed is filtered off to give 4.48 g of theexpected product.

NMR spectrum at 200 MHz in DMSO-d₆

1.3 ppm: mt: 4H

2.5 ppm: mt: 4H

4.2 ppm: broad signal: 4H

6.5 to 8.2 ppm: m: 7H

B) 3-4-(tert-Butoxycarbonylamino)butyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

1.95 ml of triethylamine and then 3.074 g of di-tert-butyl dicarbonateare added at RT to a suspension of 5.13 g of the compound obtained inthe previous step in 150 ml of THF and the mixture is stirred for 20hours at RT. An insoluble material is filtered off and the filtrate isconcentrated under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/AcOEt mixture (75/25; v/v) as the eluent togive 2.8 g of the expected product after crystallization from a DCM/isoether mixture. M.p.=175°-176° C.

Preparation 43 3-5-(tert-Butoxycarbonylamino)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) 5-(tert-Butoxycarbonylamino)pentyl methanesulfonate

A solution of 28.6 g of 5-(tert-butoxycarbonylamino)pentan-1-ol in 100ml of pyridine is cooled to 0° C. and 16.2 g of methanesulfonyl chlorideare added dropwise in 3 hours at 0° C. The reaction mixture is stirredovernight at RT and concentrated under vacuum. The residue is taken upwith water and extracted with AcOEt, the organic phase is washed threetimes with water, three times with a 5% solution of potassiumhydrogensulfate, three times with water and with a saturated solution ofNaCl and dried over sodium sulfate and the solvent is evaporated offunder vacuum to give 39 g of the expected product, which is used as suchin the next step.

B) 5-(tert-Butoxycarbonylamino)pentyl azide

A mixture of 39 g of the compound obtained in the previous step, 9 g ofsodium azide and 80 ml of DMSO is heated at 80° C. for 5 hours. Thereaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed with water and with a saturated solution of NaCland dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a hexane/AcOEtmixture (90/10; v/v) as the eluent to give 7.8 g of the expectedproduct, which is used as such in the next step.

C) 5-(tert-Butoxycarbonylamino)pentylamine

1.5 ml of hydrazine monohydrate are added to a mixture of 7.8 g of thecompound obtained in the previous step, 1.5 g of Raney® nickel and 60 mlof EtOH and the reaction mixture is stirred for 1 hour 30 minutes at RT.A further 1.5 ml of hydrazine monohydrate are added and the mixture isstirred for 1 hour 30 minutes at RT. The catalyst is filtered off andthe filtrate is concentrated under vacuum. The residue is taken up withwater and acidified to pH 1 by the addition of a 1N solution of HCl, theaqueous phase is washed with ether, rendered alkaline by the addition ofpotassium carbonate and extracted four times with ether, the organicphase is washed with water and with a saturated solution of NaCl anddried over sodium sulfate and the solvent is evaporated off under vacuumto give 3.0 g of the expected product, which is used as such in the nextstep.

D) 3-5-(tert-Butoxycarbonylamino)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 2.65 g of the compound obtained in step C of Preparation 2,3 g of the compound obtained in the previous step and 30 ml ofchloroform is stirred for 3 hours at RT. The reaction mixture isconcentrated under vacuum, the residue is taken up with water andextracted with AcOEt, the organic phase is washed with a 5% solution ofpotassium carbonate, with water and with a saturated solution of NaCland dried over sodium sulfate and the solvent is partially evaporatedoff under vacuum. The crystalline product formed is filtered off to give2.14 g of the expected product, a sample of which is recrystallized froma THF/iso ether mixture. M.p.=185° C.

Preparation 44 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(piperid-1-yl)ethyl!amino!indol-2-one

3.23 g of 1-(2-aminoethyl)piperidine are added at RT to a solution of 5g of the compound obtained in step C of Preparation 2 in 120 ml ofchloroform and the reaction mixture is stirred for 2 hours at RT. It iswashed with water and, after decantation, the organic phase is driedover sodium sulfate and the solvent is evaporated off under vacuum togive 4.8 g of the expected product after crystallization from an isoether/hexane/pentane mixture; it is used as such in EXAMPLE 167.

Preparations 45 and 46 3- 2-4-(Benzyloxycarbonyl)piperazin-1-yl!-ethyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one(Preparation 45) and 3- 4-2-(benzyloxycarbonylamino)ethyl!piperazin-1-yl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one (Preparation 46) A)5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(piperazin-l-yl)ethyl!amino!indol-2-one and 3-4-(2-aminoethyl)piperazin-1-yl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 3 g of the compound obtained in step C of Preparation 2 in30 ml of chloroform and 20 ml of THF is added in 1 hour at RT to asolution of 4.35 g of 1-(2-aminoethyl)piperazine in 70 ml of chloroform.After stirring for 1 hour at RT, the reaction mixture is concentratedunder vacuum. The residue is taken up with a 5% solution of potassiumcarbonate and extracted with AcOEt, the organic phase is washed withwater and with a saturated solution of NaCl and dried over sodiumsulfate and the solvent is evaporated off under vacuum to give 3.6 g ofa mixture of the two products in the form of an oil, which is used assuch in the next step.

B) 3- 2-4-(Benzyloxycarbonyl)piperazin-1-yl!ethyl!-amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one(Preparation 45) and 3- 4-2-(benzyloxycarbonylamino)ethyl!piperazin-l-yl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one(Preparation 46)

A solution of 3.6 g of the mixture of the two compounds obtained in theprevious step in 15 ml of DCM is cooled to 0° C. and 1.1 g of DIPEA andthen 1.45 g of benzyl chloroformate are added. The reaction mixture isstirred for 60 hours at RT and concentrated under vacuum. The residue isextracted with AcOEt, the organic phase is washed with water and with asaturated solution of NaCl and dried over sodium sulfate and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 0.86 g ofthe compound of Preparation 45. Elution with AcOEt then gives 1.7 g ofthe compound of Preparation 46.

NMR spectrum at 200 MHz in DMSO-d. of the compound of Preparation 45

2.0 to 3.6 ppm: m: 13H

5.1 ppm: s: 2H

6.6 to 8.2 ppm: m: 12H

10.8 ppm: s: 1H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of Preparation 46

2.0 to 3.0 ppm: m: 10H

3.15 ppm: qd: 2H

5.05 ppm: s: 2H

6.7 to 8.2 ppm: m: 13H

10.85 ppm: s: 1H

The compound of Preparation 45 can also be obtained by following the twosteps of the method described below.

A') 4-(2-Aminoethyl)-l-(benzyloxycarbonyl)piperazine

8.21 g of benzaldehyde are added to a solution of 10 g of1-(2-aminoethyl)piperazine in 125 ml of toluene and the mixture isrefluxed for 3 hours, the water formed being removed by means of aDean-Stark apparatus. The reaction mixture is concentrated under vacuum,the residue is taken up with 100 ml of DCM, 13.45 ml of DIPEA are addedand 11.03 ml of benzyl chloroformate are added dropwise. The reactionmixture is stirred overnight at RT and concentrated under vacuum. Theresidue is taken up with a saturated solution of potassiumhydrogensulfate and stirred vigorously for 4 hours at RT. The aqueousphase is washed with ether, rendered alkaline to pH 9-10 by the additionof concentrated NaOH, saturated by the addition of NaCl and extractedwith chloroform, the organic phase is dried over sodium sulfate and thesolvent is evaporated off under vacuum to give 18.78 g of the expectedproduct, which is used as such in the next step.

B') 3- 2-4-(Benzyloxycarbonyl)piperazin-1-yl!ethyl!-amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 1.77 g of the compound obtained in the previous step and3.1 ml of triethylamine in 10 ml of chloroform is added dropwise at RTto a solution of 2 g of the compound obtained in step C of Preparation 2in 20 ml of chloroform and 3 ml of THF and the mixture is stirred for 3hours at RT. It is concentrated under vacuum, the residue is extractedwith AcOEt, the organic phase is washed with a saturated solution ofNaCl and with water and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/AcOEt mixture (40/60; v/v) as the eluent togive 2 g of the expected product.

Preparation 47 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(morpholin-4-yl)ethyl!amino!indol-2-one

A mixture of 5 g of the compound obtained in step C of Preparation 2,3.5 g of 4-(2-aminoethyl)-morpholine and 120 ml of chloroform is stirredfor 2 hours at RT. The reaction mixture is washed with water and, afterdecantation, the organic phase is dried over sodium sulfate and thesolvent is evaporated off under vacuum to give 5.2 g of the expectedproduct after trituration in a hexane/pentane mixture followed byfiltration. It is used as such.

Preparation 48 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-3-(morpholin-4-yl)propyl!amino!indol-2-one

A solution of 3.57 g of the compound obtained in step C of Preparation 2in 100 ml of chloroform is cooled to 0° C. and a solution of 1.44 g of4-(3-aminopropyl)morpholine and 2.02 g of triethylamine in 10 ml ofchloroform is added dropwise in 10 minutes. The reaction mixture isstirred overnight at RT and concentrated under vacuum. The residue istaken up with water, rendered alkaline to pH 10 by the addition ofpotassium carbonate and extracted with AcOEt, the organic phase iswashed with water and with a saturated solution of NaCl and dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using an AcOEt/MeOH mixture (93/7;v/v) as the eluent to give 2.8 g of the expected product in the form ofa foam after crystallization from a DCM/hexane mixture followed bydrying at 90° C. under vacuum.

NMR spectrum at 200 MHz at DMSO-d₆

1.6 ppm: mt: 2H

2.1 to 2.6 ppm: m: 8H

3.35 ppm: t: 1H

3.55 ppm: t: 4H

6.6 to 8.3 ppm: m: 7H

10.8 ppm: s: 1H

Preparation 49 3-2-(tert-Butoxycarbonylamino)-2-methylpropyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 1.17 ml of 1,2-diamino-2-methylpropane and 2.32 ml oftriethylamine in 15 ml of chloroform is added dropwise at RT to asolution of 2 g of the compound obtained in step C of Preparation 2 in20 ml of chloroform and the reaction mixture is stirred for 3 hours atRT. It is concentrated under vacuum, the residue is dissolved in 15 mlof DCM, 1.57 ml of triethylamine and then 1.45 g of di-tert-butyldicarbonate are added and the reaction mixture is stirred for 18 hoursat RT. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed with a saturated solution of NaCl andwith water and dried over sodium sulfate and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica using DCM andthen a DCM/MeOH mixture (85/15; v/v) as the eluent to give 1.4 g of theexpected product after crystallization from a DCM/iso ether mixture.M.p.=164° C.

Preparation 50 5-Chloro-3-(2-chlorophenyl)-3-(diethylaminocarbonyl)methyl!amino!-1,3-dihydroindol-2-one A) tert-ButylN- 5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-3-yl!glycinate

A mixture of 6 g of the compound obtained in step C of Preparation 2, 4g of tert-butyl glycinate and 100 ml of chloroform is stirred for 18hours at RT. The reaction mixture is washed with water and, afterdecantation, the organic phase is dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give2.7 g of the expected product after crystallization from a DCM/iso ethermixture. M.p.=217° C.

B) N- 5-Chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-3-yl!glycine

12 ml of TFA are added to a mixture of 2.7 g of the compound obtained inthe previous step in 12 ml of DCM and the reaction mixture is stirredfor 18 hours at RT. It is concentrated under vacuum at 35° C., theresidue is taken up with an ether/hexane mixture and the precipitateformed is filtered off to give 2.5 g of the expected product, which isused as such in the next step.

C) 5-Chloro-3-(2-chlorophenyl)-3-(diethylaminocarbonyl)methyl!amino!-1,3-dihydroindol-2-one

1.3 g of BOP are added to a solution of 1 g of the compound obtained inthe previous step and 0.66 g of diethylamine in 10 ml of DMF and themixture is stirred for 18 hours at RT. Water is added to the reactionmixture and the precipitate formed is filtered off and washed withwater. The precipitate is dissolved in DCM, the organic phase is washedwith water and dried over sodium sulfate and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica using aDCM/AcOEt mixture (50/50; v/v) as the eluent to give 0.95 g of theexpected product after crystallization from a DCM/iso ether mixture.M.p.=223° C.

Preparation 51 5-Chloro-3-(2-chlorophenyl)-3-2-(diethylaminocarbonyl)ethyl!amino!-1,3-dihydroindol-2-one A)tert-Butyl N-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-3-yl!-β-alaninate

3.2 g of tert-butyl β-alaninate hydrochloride and then 4.18 g of DIPEAare added at RT to a solution of 6 g of the compound obtained in step Cof Preparation 2 in 100 ml of chloroform and the reaction mixture isstirred for 2 hours at RT. It is washed with water and, afterdecantation, the organic phase is dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using a DCM/AcOEt mixture (85/15; v/v) as the eluent to give 5g of the expected product after crystallization from a DCM/iso ethermixture. M.p.=188° C.

B) N- 5-Chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-3-yl!-β-alanine

4.7 g of the compound obtained in the previous step and 50 ml of TFA aremixed at 0° C. and the mixture is stirred for 5 hours, the temperaturebeing allowed to rise to RT. The reaction mixture is concentrated undervacuum at 30° C., the residue is taken up with an ether/hexane mixtureand the precipitate formed is filtered off to give 1.5 g of the expectedproduct, which is used as such in the next step.

C) 5-Chloro-3-(2-chlorophenyl)-3-2-(diethylaminocarbonyl)ethyl!amino!-1,3-dihydroindol-2-one

A solution of 1.5 g of the compound obtained in the previous step and0.906 g of diethylamine in 20 ml of DMF is cooled to 0° C., 1.4 g of BOPare added and the mixture is stirred for 18 hours, the temperature beingallowed to rise to RT. The reaction mixture is poured into water and theprecipitate formed is filtered off. The precipitate is dissolved inAcOEt, the organic phase is washed with water and dried over sodiumsulfate and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using a DCM/AcOEt mixture (50/50; v/v) as theeluent to give 0.82 g of the expected product after crystallization froma DCM/iso ether mixture. M.p.=185° C.

Preparation 52 5-Chloro-3-(2-chlorophenyl)-3-3-(methoxycarbonyl)propyl!amino!-1,3-dihydroindol-2-one

A mixture of 2 g of the compound obtained in step C of Preparation 2,1.65 g of methyl 4-aminobuty-rate hydrochloride, 2.09 g of DIPEA and 20ml of chloroform is stirred for 1 hour at RT. The reaction mixture iswashed with a 5% solution of sodium carbonate and, after decantation,the organic phase is dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing an AcOEt/hexane mixture (50/50; v/v) as the eluent to give 1.7 gof the expected product after crystallization from a DCM/iso ethermixture. M.p.=142° C.

Preparation 53 5-Chloro-3-(2-chlorophenyl)-3-(cyanomethyl)-amino!-1,3-dihydroindol-2-one

A solution of 3 g of the compound obtained in step C of Preparation 2 in20 ml of chloroform and 20 ml of THF is cooled to +4° C., a solution of0.92 g of aminoacetonitrile hydrochloride and 4.6 ml of triethylamine in20 ml of chloroform is added dropwise and the mixture is stirred for 3hours, the temperature being allowed to rise to RT. 100 ml of water areadded to the reaction mixture, the solvents are concentrated undervacuum, the aqueous phase is extracted with AcOEt, the organic phase iswashed with a saturated solution of NaCl and with water and dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using DCM and then a DCM/AcOEtmixture (95/5; v/v) as the eluent to give 1.2 g of the expected product.M.p.=240°-241° C.

Preparations 54 and 55 3-(1S)-5-(Benzyloxycarbonylamino)-l-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one,isomer A and isomer B

A solution of 4.6 g of triethylamine in 30 ml of THF is added dropwiseat RT to a mixture of 5.4 g of the compound obtained in step C ofPreparation 2, 5 g of N-ε-(benzyloxycarbonyl)-L-lysine methyl esterhydrochloride and 30 ml of THF and the reaction mixture is stirred for 2hours at RT. It is concentrated under vacuum, the residue is taken upwith a 5% solution of sodium carbonate and extracted with AcOEt, theorganic phase is washed with water and dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using a gradient of a hexane/AcOEt mixture (from 95/5; v/v to50/50; v/v) as the eluent. The two isomers are separated out:

the less polar isomer, A: compound of Preparation 54, which isrechromatographed on silica using a DCM/AcOEt mixture (60/40; v/v) asthe eluent. α_(D) ²⁵ =+105° (c=0.257; chloroform);

the more polar isomer, B: compound of Preparation 55, which isrechromatographed on silica using a DCM/AcOEt mixture (50/50; v/v) asthe eluent. α_(D) ²⁵ =-95.7° (c=0.279; chloroform).

Preparations 56 and 57 3-(1R)-5-(Benzyloxycarbonylamino)-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one,isomer A and isomer B

These two compounds are prepared according to the procedure described inPreparations 54 and 55 from 4.1 g of the compound obtained in step C ofPreparation 2 and 5.22 g of N-ε-(benzyloxycarbonyl)-D-lysine methylester hydrochloride in 40 ml of THF and 4.2 g of triethylamine in 30 mlof THF. Chromatography on silica using a gradient of a pentane/AcOEtmixture (from 95/5; v/v to 45/55; v/v) as the eluent separates out oneisomer:

the less polar isomer, A: compound of Preparation 56. α_(D) ²⁵ =-100.7(c=0.275; chloroform).

The remaining product is rechromatographed on silica H using a gradientof a DCM/AcOEt mixture (from 94/6; v/v to 75/25; v/v) as the eluent toseparate out the other isomer:

the more polar isomer, B: compound of Preparation 57. α_(D) ²⁵ =+92.9°(c=0.254; chloroform).

Preparations 58 and 59 3-(1S)-5-(Benzyloxycarbonylamino)-1-(hydroxymethyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one,isomer A and isomer B A) N-ε-(Benzyloxycarbonyl)-L-lysinol

5 g of N-ε-(benzyloxycarbonyl)-L-lysine methyl ester hydrochloride areadded in 10 minutes to a suspension of 5 g of sodium borohydride in 100ml of EtOH and the mixture is stirred overnight at RT. 10 ml of a 5Nsolution of HCl are added and the solvent is evaporated off undervacuum. The residue is taken up with water, the aqueous phase isrendered alkaline to pH 13 by the addition of concentrated NaOH andextracted with AcOEt, the organic phase is washed twice with water andwith a saturated solution of NaCl and dried over sodium sulfate and thesolvent is evaporated off under vacuum to give 3.58 g of the expectedproduct, which is used as such.

B) 3-(1S)-5-(Benzyloxycarbonylamino)-1-(hydroxymethyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one,isomer A and isomer B

A solution of 3.50 g of the compound obtained in the previous step and 4g of triethylamine in 40 ml of THF is added dropwise to a solution of4.90 g of the compound obtained in step C of Preparation 2 in 50 ml ofTHF and the mixture is stirred for 2 hours at RT. A 5% solution ofpotassium carbonate is added, extraction is carried out with AcOEt, theorganic phase is washed with water and with a saturated solution of NaCland dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a DCM/AcOEtmixture (60/40; v/v) as the eluent to separate out one isomer:

the less polar isomer, A: compound of Preparation 58, which isrechromatographed on alumina using an AcOEt/MeOH mixture (97/3; v/v) asthe eluent to give 2.4 g of the product in the form of an oil. α_(D) ²⁵=+174.3° (c=0.25; chloroform).

Elution in the 1st chromatography with a DCM/AcOEt mixture (20/80; v/v)separates out the other isomer:

the more polar isomer, B: compound of Preparation 59, which is taken upwith a hexane/iso ether mixture and then, after filtration of theprecipitate formed, crystallized from a DCM/iso ether mixture to give1.3 g. M.p.=110° C. α_(D) ²⁵ =-95.2° (c=0.25; chloroform).

Preparation 60 3- (1S)-5-(Benzyloxycarbonylamino)-1-(trimethylsilyloxy)methyl!pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 2.1 g of the compound obtained in Preparation 58 (isomerA), 0.63 g of hexamethyldisilane, 0.025 g of zinc chloride and 20 ml ofacetonitrile is heated at 60° C. overnight. It is concentrated undervacuum, the residue is extracted with AcOEt, the organic phase israpidly washed twice with water and with a saturated solution of NaCland dried over sodium sulfate and the solvent is evaporated off undervacuum to give the expected product, which is used as such in EXAMPLE226.

Preparation 61 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(dimethylamino)acetamido!indol-2-one

A mixture of 1.07 g of the compound obtained in Preparation 2, 0.32 mlof bromoacetyl bromide and 15 ml of benzene is refluxed for 1 hour.After cooling, the precipitate formed is filtered off. The precipitateis taken up with 10 ml of DCM, 3 ml of a 30% solution of dimethylaminein EtOH are added in 1 hour and the reaction mixture is stirred. It isconcentrated under vacuum, the residue is taken up with a 5% solution ofsodium carbonate and extracted with AcOEt, the organic phase is washedwith water and with a saturated solution of NaCl and dried over sodiumsulfate and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using an AcOEt/MeOH mixture (90/10; v/v) asthe eluent to give 0.63 g of the expected product after crystallizationfrom an AcOEt/MeOH mixture. M.p.=236°-238° C.

Preparation 62 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(4-methylpiperazin-1-yl)acetamido!indol-2-one A)5-Chloro-3-(2-chloroacetamido)-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 8 g of the compound obtained in Preparation 2 and 300 ml ofbenzene is heated to the reflux point, 3.4 g of chloroacetyl chlorideare added and the reaction mixture is stirred for 2 hours under reflux.It is concentrated under vacuum and the residue is crystallized from aDCM/iso ether mixture to give 8 g of the expected product. M.p.=230° C.

B) 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(4-methylpiperazin-1-yl)acetamido!indol-2-one

A mixture of 1.4 g of the compound obtained in the previous step, 0.455g of 1-methylpiperazine, 0.523 g of potassium carbonate, 0.01 g ofsodium iodide and 20 ml of DMF is heated at 60° C. for 1 hour. Thereaction mixture is concentrated under vacuum, the residue is taken upwith water and extracted with AcOEt, the organic phase is dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using a DCM/MeOH mixture (96/4;v/v) as the eluent to give 1.2 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=214° C.

Preparation 63 5-Chloro-3-(2-chlorophenyl)-3-3-(diethylamino)propionamido!-1,3-dihydroindol-2-one

0.43 ml of acryloyl chloride is added to a solution of 1.5 g of thecompound obtained in Preparation 2 in 5 ml of pyridine and the mixtureis stirred for 12 hours at RT. A further 0.43 ml of acryloyl chloride isadded and stirring is continued for 12 hours. The reaction mixture isconcentrated under vacuum, the residue is taken up with water andextracted with AcOEt, the organic phase is washed with a 1N solution ofHCl and with water and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is dissolved in 5 ml of EtOH,and 0.5 g of diethylamine is added in 4 days at RT. The mixture isconcentrated under vacuum, the residue is taken up with a 1N solution ofHCl, the aqueous phase is washed with AcOEt, rendered alkaline to pH 10by the addition of a 5% solution of potassium carbonate and extractedwith AcOEt, the organic phase is washed with water and with a saturatedsolution of NaCl and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing a DCM/MeOH/NH₄ OH mixture (80/15/5; v/v/v) as the eluent to give0.335 g of the expected product.

NMR spectrum at 200 MHz in DMSO-d₆

0.85 ppm: t: 6H

2.0 to 2.8 ppm: m: 8H

6.7 to 7.7 ppm: m: 7H

9.3 ppm: s: 1H

10.9 ppm: s: 1H

Preparation 64 5-Chloro-3-(2-chlorophenyl)-3-3-(diethylamino)propionamido!-1,3-dihydroindol-2-one, (+) isomer

A solution of 1.88 g of the compound obtained in Preparation 28, (+)isomer, in 8 ml of pyridine is cooled to 0° C., 1.225 g of acryloylchloride are added dropwise and the mixture is stirred for 72 hours atRT. Water is added to the reaction mixture, extraction is carried outwith AcOEt, the organic phase is washed with water and with a saturatedsolution of NaCl and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is dissolved in 5 ml of EtOH,2.346 g of diethylamine are added and the mixture is stirred for twodays at RT. It is concentrated under vacuum and the residue ischromatographed on silica using a DCM/MeOH mixture (75/25; v/v) as theeluent to give 0.350 g of the expected product after crystallizationfrom a DCM/iso ether mixture. M.p.=176°-178° C. α_(D) ²⁵ =+56.3°(c=0.38; chloroform).

Preparation 653-(2-Chlorophenyl)-1,3-dihydro-5-methyl-3-(methylamino)indol-2-one A)N-p-Methylphenyl-DL-2-chloromandelamide

A mixture of 32.1 g of p-toluidine, 55.95 g of DL-2-chloromandelic acidand 250 ml of 1,2-dichlorobenzene is refluxed for 6 hours, the waterformed being removed by means of a Dean-Stark apparatus. The reactionmixture is cooled and the precipitate formed is filtered off and washedwith iso ether to give 48 g of the expected product, which is used assuch.

B) 3-(2-Chlorophenyl)-1,3-dihydro-5-methylindol-2-one

A mixture of 86 ml of concentrated sulfuric acid and 20 ml of fumingsulfuric acid (30% oleum) is cooled to 10° C. and 20 g of the compoundobtained in the previous step are added in portions, the internaltemperature being kept below 40 C. The reaction mixture is stirred for18 hours at RT and poured onto ice and the precipitate formed isfiltered off. The precipitate is dissolved in chloroform, the organicphase is washed with water to pH 7 and dried over sodium sulfate and thesolvent is evaporated off under vacuum to give 12 g of the expectedproduct after crystallization from a THF/DCM/iso ether mixture.M.p.=208° C.

C) 3-(2-Chlorophenyl)-1,3-dihydro-3-hydroxy-5-methylindol-2-one

0.952 g of sodium hydride as a 60% dispersion in oil is added at RT to asolution of 5.6 g of the compound obtained in the previous step in 150ml of THF and the mixture is stirred for 30 minutes. 2.46 ml of dimethyldisulfide are then added and the mixture is stirred for 48 hours. Wateris added to the reaction mixture and the precipitate formed is filteredoff and washed with ether and then with pentane to give 5.1 g of theexpected product. M.p.=295°-300° C.

D) 3-Chloro-3-(2-chlorophenyl)-l,3-dihydro-5-methylindol-2-one

A suspension of 1.5 g of the compound obtained in the previous step in20 ml of DCM is cooled to +4° C., 0.84 ml of pyridine and then 0.6 ml ofthionyl chloride are added and the mixture is stirred for 3 hours at RT.It is concentrated under vacuum and the residue is chromatographed onsilica using a DCM/hexane mixture (80/20; v/v) and then DCM as theeluent to give 1.06 g of the expected product, which is used as such.

E) 3-(2-Chlorophenyl)-1,3-dihydro-5-methyl-3-(methylamino)indol-2-one

0.9 ml of an 8.03M solution of methylamine in EtOH is added at RT to asolution of 1.06 g of the compound obtained in the previous step in 5 mlof DCM and the mixture is stirred for 1 hour. It is concentrated undervacuum, the residue is extracted with AcOEt, washed with a saturatedsolution of NaCl and with water and dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using DCM and then a DCM/AcOEt mixture (75/25; v/v) as theeluent to give 0.82 g of the expected product after crystallization froma DCM/iso ether mixture. M.p.=186°-187° C.

Preparation 663-Amino-3-(2-chlorophenyl)-1,3-dihydro-5-methoxyindol-2-one

A) N-p-Methoxyphenyl-DL-2-chloromandelamide A mixture of 33.25 g ofp-anisidine, 50 g of DL-2-chloromandelic acid and 250 ml of1,2-dichlorobenzene is heated at 225° C. for 5 hours, the water formedbeing removed by means of a Dean-Stark apparatus. The reaction mixtureis concentrated to about 150 ml and left to crystallize overnight. Thecrystals formed are filtered off and washed with ether to give 43.76 gof the expected product.

B) 3-(2-Chlorophenyl)-1,3-dihydro-5-methoxyindol-2-one

A mixture of 393 g of polyphosphoric acid and 30 g of the compoundobtained in the previous step is heated at 60° C. for 4 hours. 350 g ofice are added to the reaction mixture, extraction is carried out withAcOEt, the organic phase is washed with a saturated solution of NaCl topH 7 and dried over magnesium sulfate and the solvent is evaporated offunder vacuum until the product precipitates. After filtration anddrying, 11.29 g of the expected product are obtained, which is used assuch.

C) 3-Chloro-3-(2-chlorophenyl)-1,3-dihydro-5-methoxyindol-2-one

4.9 g of N-chlorosuccinimide are added to a suspension of 9.29 g of thecompound obtained in the previous step in 100 ml of CCl₄ and the mixtureis refluxed for 3 hours. After cooling, an insoluble material isfiltered off and the filtrate is evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (98/2;v/v to 96/4; v/v) as the eluent to give 6.1 g of the expected product,which is used as such.

D) 3-Azido-3-(2-chlorophenyl)-1,3-dihydro-5-methoxyindol-2-one

3.9 g of sodium azide are added to a solution of 6.1 g of the compoundobtained in the previous step in 100 ml of acetonitrile and the mixtureis refluxed for 4 hours. It is concentrated under vacuum, the residue istaken up with water and extracted with AcOEt, the organic phase iswashed with a saturated solution of NaCl and with a 5% aqueous solutionof sodium dithionite and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/AcOEt mixture (99/1; v/v) as the eluent to give2.79 g of the expected product. Infrared spectrum in DCM: 2125 cm⁻¹.

E) 3-Amino-3-(2-chlorophenyl)-1,3-dihydro-5-methoxyindol-2-one

2.47 ml of triethylamine and then 1.78 ml of propane-1,3-dithiol areadded by syringe, under an argon atmosphere, to a solution of 2.79 g ofthe compound obtained in the previous step in 44 ml of MeOH and thereaction mixture is heated at 60° C. for 4 hours. It is concentratedunder vacuum and the residue is chromatographed on silica using DCM andthen a DCM/AcOEt mixture (70/30; v/v) as the eluent to give 1.23 g ofthe expected product after crystallization from AcOEt.

NMR spectrum at 200 MHz in DMSO-d₆

2.6 ppm: s: 2H

3.65 ppm: s: 3H

6.2 to 7.0 ppm: m: 3H

7.2 to 8.4 ppm: m: 4H

10.4 ppm: s: 1H

Preparation 673-(2-Chlorophenyl)-5-ethoxy-3-(ethylamino)-1,3-dihydroindol-2-one

5 ml of AcOH and then 0.2 ml of acetaldehyde are added at RT to asolution of 1 g of the compound obtained in Preparation 16 in 20 ml ofMeOH, and 0.293 g of sodium cyanoborohydride is added in portions. Themixture is stirred for 30 minutes at RT, 5 drops of concentrated HC1 areadded and the reaction mixture is then neutralized by the addition of a5% solution of potassium carbonate. The MeOH is evaporated off undervacuum, extraction is carried out with AcOEt, the organic phase iswashed with water and with a saturated solution of NaCl and dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on alumina using DCM and then a DCM/AcOEtmixture (95/5; v/v) as the eluent to give 0.3 g of the expected productafter crystallization from a DCM/iso ether mixture. M.p.=195°-200° C.

Preparation 683-(2-Chlorophenyl)-5-ethoxy-1,3-dihydro-3-(dimethylamino)indol-2-one

5 ml of AcOH and then 0.4 g of paraformaldehyde are added at RT to asolution of 1 g of the compound obtained in Preparation 16 in 20 ml ofMeOH, and 0.532 g of sodium cyanoborohydride is added in portions in 1hour. The mixture is stirred for 48 hours at RT, 5 drops of concentratedHCl are added and the reaction mixture is then neutralized by theaddition of a 5% solution of potassium carbonate. The MeOH is evaporatedoff under vacuum, extraction is carried out with AcOEt, the organicphase is washed with water and with a saturated solution of NaCl anddried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using DCM and then aDCM/AcOEt mixture (90/10; v/v) as the eluent to give 1 g of the expectedproduct after crystallization from a DCM/iso ether mixture (product inthe form of a foam after drying at 90° C. under vacuum).

NMR spectrum at 200 MHz in DMSO-d₆

1.15 ppm: t: 3H

2.1 ppm: bs: 6H

3.75 ppm: qd: 2H

6.1 to 8.1 ppm: m: 7H

10.4 ppm: s: 1H

Preparation 693-(2-Chlorophenyl)-5-fluoro-1,3-dihydro-3-(methylamino)indol-2-one A)N-p-Fluorophenyl-DL-2-chloromandelamide

This compound is prepared according to the procedure described in step Aof Preparation 2 from 4-fluoroaniline and DL-2-chloromandelic acid.

B) 3-(2-Chlorophenyl)-5-fluoro-1,3-dihydroindol-2-one

40 ml of fuming sulfuric acid (30% oleum) are added dropwise to 160 mlof concentrated sulfuric acid. 40 g of the compound obtained in theprevious step are then added in portions, the internal temperature beingkept below 40° C., and the reaction mixture is stirred for 16 hours atRT. It is poured onto 300 g of ice and extracted with AcOEt, the organicphase is washed with a saturated solution of NaCl and dried over sodiumsulfate and the solvent is evaporated off under vacuum to give 42 g ofthe expected product, which is used as such.

C) 3-Bromo-3-(2-chlorophenyl)-5-fluoro-1,3-dihydroindol-2-one

A solution of 0.78 ml of bromine in 1 ml of chloroform is added dropwiseto a suspension of 4.0 g of the compound obtained in the previous stepin 100 ml of chloroform and the mixture is stirred for 30 minutes at RT.It is concentrated under vacuum, the residue is taken up with DCM andthe solvent is evaporated off under vacuum to give 5.2 g of the expectedproduct, which is used as such.

D) 3-(2-Chlorophenyl)-5-fluoro-1,3-dihydro-3-(methylamino)indol-2-one

2.8 ml of a 33% solution of methylamine in EtOH are added dropwise to asuspension of 5.2 g of the compound obtained in the previous step in 100ml of DCM and the mixture is stirred for 2 hours at RT. It isconcentrated under vacuum and extracted with AcOEt, the organic phase iswashed with a 5% solution of sodium carbonate and with a saturatedsolution of NaCl and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/MeOH mixture (98/2; v/v) as the eluent to give2.15 g of the expected product after crystallization from a DCM/isoether mixture. M.p.=188°-189° C.

Preparations 70 and 715-Chloro-3-(2-chlorophenyl)-1,3-dihydro-4-methyl-3-(methylamino)indol-2-one(Preparation 70) and5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methyl-3-(methylamino)indol-2-one(Preparation 71) A)5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-4-methylindol-2-one and5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one

A mixture of these two compounds is prepared according to the proceduredescribed in step B of Preparation 2 fromN-(4-chloro-3-methylphenyl)-DL-2-chloromandelamide, itself obtainedaccording to the procedure described in step A of Preparation 2 from4-chloro-3-methylaniline and DL-2-chloromandelic acid.

B) 3-Bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-4-methylindol-2-oneand 3-bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one

A solution of 0.6 ml of bromine in 60 ml of DCM is added dropwise at RTto a suspension of 3.62 g of the mixture of the two compounds obtainedin the previous step in 60 ml of DCM and the mixture is stirred for 30minutes at RT. It is concentrated under vacuum, the residue is taken upwith DCM and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using a DCM/AcOEt mixture (97/3; v/v) as theeluent to give 5.42 g of the mixture of the two expected products, whichis used as such.

C)5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-4-methyl-3-(methylamino)indol-2-one(Preparation 70) and5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methyl-3-(methylamino)indol-2-one(Preparation 71)

2 ml of an 8.03M solution of methylamine in EtOH are added to a solutionof 2.94 g of the mixture of the two compounds obtained in the previousstep in 100 ml of EtOH and the mixture is stirred overnight at RT. It isconcentrated under vacuum, the residue is taken up with 100 ml of a 5%solution of sodium carbonate and extracted four times with DCM, theorganic phase is dried over sodium sulfate and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica using aDCM/AcOEt mixture (90/10; v/v) as the eluent to give the product ofPreparation 70 after crystallization from a DCM/THF/iso ether mixture.Elution with a DCM/AcOEt mixture (75/25; v/v) then gives the product ofPreparation 71 after crystallization from a DCM/THF/iso ether mixture.

the less polar compound: compound of Preparation 70.

NMR spectrum at 200 MHz in DMSO-d₆

1.8 ppm: s: 3H

2.1 ppm: d: 3H

3.1 ppm: qd: 1H

6.7 to 8.3 ppm: m: 6H

10.8 ppm: s: 1H

the more polar compound: compound of Preparation 71. M.p.=234° C.

The compound of Preparation 71 can also be obtained by following thethree steps of the method described below.

A') 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one

This compound is prepared according to the procedure described in step Aabove from 35 g of N-(4-chloro-3-methylphenyl)-DL-2-chloromandelamide.Crystallization of the mixture obtained in step A above from AcOEt,followed by recrystallization from a DCM/THF/AcOEt mixture, gives 8.1 gof the expected product. M.p.=203°-209° C.

B') 3-Bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one

This compound is prepared according to the procedure described in step Babove from 8 g of the compound obtained in step A'. After concentrationof the reaction mixture under vacuum, the residue is taken up with DCMand the precipitate formed is filtered off to give 6.0 g of the expectedproduct. The filtrate is chromatographed on silica using a DCM/hexanemixture (30/70; v/v) as the eluent to give 1.42 g of the expectedproduct in a second crop after crystallization from DCM. M.p.=109°-111°C.

C')5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methyl-3-(methylamino)indol-2-one

This compound is prepared according to the procedure described in step Cabove from the compound obtained in step B'.

Preparation 72 3-2-(1-tert-Butoxycarbonylpiperid-4-yl)-ethyl!amino!-5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) N-3,4-Dichlorophenyl-DL-2-chloromandelamide

This compound is prepared according to the procedure described in step Aof Preparation 2 from 3,4-dichloroaniline and DL-2-chloromandelic acid.M.p.=160°-163° C.

B) 5,6-Dichloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 53 ml of concentrated sulfuric acid and 12 ml of fumingsulfuric acid (30% oleum) is cooled to 0° C. and 13 g of the compoundobtained in the previous step are added in portions. The reactionmixture is stirred for 24 hours at RT and poured into water and theprecipitate formed is filtered off. The precipitate is dissolved inAcOEt, the organic phase is washed with water to pH 7 and dried oversodium sulfate and the solvent is partially evaporated off under vacuum.The crystalline product formed is filtered off and recrystallized from aTHF/DCM/AcOEt mixture to give 1.3 g of the expected product.M.p.=198°-201° C.

C) 3-Bromo-5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 0.32 g of bromine in 1 ml of chloroform is added dropwiseto a suspension of 1.95 g of the compound obtained in the previous stepin 30 ml of chloroform and the mixture is stirred for 30 minutes at RT.It is concentrated under vacuum, the residue is taken up with DCM andthe solvent is evaporated off under vacuum. The residue is extractedwith AcOEt, the organic phase is washed with water to pH 7 and driedover sodium sulfate and the solvent is evaporated off under vacuum togive the expected product after crystallization from DCM. M.p.=215°-218°C.

D) 4-(2-Aminoethyl)-1-(tert-butoxycarbonyl)piperidine a)1-(tert-Butoxycarbonyl)-4-(2-hydroxyethyl)-piperidine

A solution of 87 g of di-tert-butyl dicarbonate in 100 ml oftert-butanol is added dropwise at RT to a solution of 51 g of4-(2-hydroxyethyl)piperidine in 20 ml of tert-butanol and the mixture isstirred overnight at RT. It is concentrated under vacuum, the residue isextracted with AcOEt, the organic phase is washed with a buffer solutionof pH 2 and dried over sodium sulfate and the solvent is evaporated offunder vacuum to give 91.5 g of the expected product, which is used assuch.

b) 2-(1-tert-Butoxycarbonylpiperid-4-yl)ethyl methanesulfonate

A solution of 86.8 g of the compound obtained in the previous step in400 ml of DCM is cooled to 0° C., a solution of 53 ml of triethylaminein 20 ml of DCM and then a solution of 33 ml of methanesulfonyl chloridein 20 ml of DCM are added and the reaction mixture is stirred for 5hours. It is washed with water and, after decantation, the organic phaseis dried over sodium sulfate and the solvent is evaporated off undervacuum to give the expected product, which is used as such.

c) 2-(1-tert-Butoxycarbonylpiperid-4-yl)ethyl azide

A mixture of 5 g of the compound obtained in the previous step, 1.2 g ofsodium azide and 15 ml of DMSO is heated at 50° C. for 4 hours. Thereaction mixture is poured into water, extracted with AcOEt and driedover sodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using a hexane/AcOEt mixture(90/10; v/v) as the eluent to give 2.8 g of the expected product, whichis used as such in the next step.

d) 4-(2-Aminoethyl)-1-(tert-butoxycarbonyl)-piperidine

A mixture of 2.8 g of the compound obtained in the previous step, 0.5 gof Raney® nickel, 0.54 ml of hydrazine monohydrate and 20 ml of EtOH isstirred for 4 hours at RT. A further 0.54 ml of hydrazine monohydrate isadded in 4 hours and the mixture is stirred for 48 hours at RT. Thecatalyst is filtered off and the filtrate is concentrated under vacuumto give 2.3 g of the expected product, which is used as such.

E) 3-2-(1-tert-Butoxycarbonylpiperid-4-yl)ethyl!-amino!-5,6-dichloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 1.05 g of4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperidine and 0.46 g oftriethylamine in 10 ml of chloroform is added at RT to a solution of 1.8g of the compound obtained in step C in 50 ml of THF and the mixture isstirred for 2 hours at RT. It is concentrated under vacuum, the residueis taken up with a 5% solution of potassium carbonate and extracted withAcOEt, the organic phase is washed with water and with a saturatedsolution of NaCl, boiling THF is added to the organic phase, the latteris dried over sodium sulfate and the solvents are partially evaporatedoff. The crystalline product formed is filtered off to give 1.94 g ofthe expected product. M.p.=248°-249° C.

Preparation 735-Chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-3-(methylamino)indol-2-oneA) N-(4-Chloro-2-fluorophenyl)-DL-2-chloromandelamide

This compound is prepared according to the procedure described in step Aof Preparation 2 from 4-chloro-2-fluoroaniline and DL-2-chloromandelicacid.

B) 5-Chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-indol-2-one

30 ml of concentrated sulfuric acid are cooled to +4° C., 7.5 ml offuming sulfuric acid (30% oleum) are added and 7 g of the compoundobtained in the previous step are then added in portions. The mixture isstirred for 48 hours at RT and 300 ml of water are added to the reactionmixture. Extraction is carried out with AcOEt, the organic phase iswashed with a saturated solution of NaCl and with water and dried oversodium sulfate and the solvent is evaporated off under vacuum to give3.4 g of the expected product after crystallization from AcOEt.

C) 3-Bromo-5-chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydroindol-2-one

0.53 ml of bromine is added to a suspension of 3.4 g of the compoundobtained in the previous step in 20 ml of chloroform and the mixture isstirred for 3 hours at RT. It is concentrated under vacuum, the residueis taken up with DCM and the solvent is evaporated off under vacuum togive 4.2 g of the expected product, which is used as such.

D)5-Chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-3-(methylamino)indol-2-one

2.7 ml of an 8.03M solution of methylamine in EtOH, diluted in 5 ml ofDCM, are added dropwise at RT to a solution of 4.2 g of the compoundobtained in the previous step in 25 ml of DCM and the reaction mixtureis stirred for 3 hours at RT. It is concentrated under vacuum, theresidue is taken up with a 5% solution of sodium carbonate and extractedwith AcOEt, the organic phase is washed with a saturated solution ofNaCl and with water and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing a DCM/AcOEt mixture (85/15; v/v) as the eluent to give 1.1 g ofthe expected product after crystallization from a DCM/THF/AcOEt mixture.M.p.=219° C.

Preparation 74 5-Chloro-3-(2-chlorophenyl)-3-2-(diethylamino)-2-methylpropyl!amino!-1,3-dihydroindol-2-one A)2-(Diethylamino)-2-methylpropylamine

This compound is prepared according to the procedure described in patentapplication EP 0429344.

B) 5-Chloro-3-(2-chlorophenyl)-3-2-(diethylamino)-2-methylpropyl!amino!-1,3-dihydroindol-2-one

A solution of 2.42 g of the compound obtained in the previous step and1.41 g of triethylamine in 30 ml of chloroform is cooled to 0° C., 5 gof the compound obtained in step C of Preparation 2 are added inportions and the reaction mixture is stirred for 18 hours at RT. It iswashed with water and, after decantation, the organic phase is driedover sodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using AcOEt as the eluent to give2.4 g of the expected product after crystallization from ether.M.p.=174° C.

Preparation 75 3- 2-N-(tert-Butoxycarbonylmethyl)-N-methylamino!acetamido!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 1.5 g of the compound obtained in step A of Preparation 62,0.957 g of tert-butyl sarcosinate hydrochloride, 1.2 g of DIPEA, 0.01 gof sodium iodide and 20 ml of acetone is refluxed for 18 hours. It isconcentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with water and dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using a DCM/AcOEt mixture (70/30; v/v) as the eluent to give1.7 g of the expected product after crystallization from a DCM/iso ethermixture. M.p.=200° C.

Preparation 765-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one,(+) isomer

0.6 g of paraformaldehyde and 0.6 g of sodium cyanoborohydride are addedin portions in 48 hours to a solution of 1.5 g of the compound obtainedin Preparation 28, (+) isomer, in 30 ml of MeOH and 20 ml of AcOH. 5drops of concentrated HCl are added, the mixture is then renderedalkaline to pH 10 by the addition of a 5% solution of potassiumcarbonate, the MeOH is evaporated off under vacuum, the aqueous phase isextracted with AcOEt, the organic phase is washed with water and with asaturated solution of NaCl and dried over sodium sulfate and the solventis evaporated off under vacuum. The residue is chromatographed onalumina using a DCM/MeOH mixture (60/40; v/v) as the eluent to give 0.62g of the expected product after crystallization from a DCM/hexanemixture. M.p.=169°-172° C. α_(D) ²⁵ =+325° (c=0.26; chloroform).

NMR spectrum at 200 MHz in DMSO-d₆

2.2 ppm: bs: 6H

6.7 to 8.2 pp: m: 7H

10.85 ppm: s: 1H

Preparation 77 3-2-(1-tert-Butoxycarbonylpiperid-4-yl)-ethyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one

A solution of 1.35 g of4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperidine and 1.75 g oftriethylamine in 20 ml of THF is added dropwise at RT to a solution of2.1 g of3-bromo-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one,obtained in step B' of Preparation 71, in 20 ml of THF and the reactionmixture is stirred for 1 hour at RT. It is concentrated under vacuum,the residue is taken up with 400 ml of AcOEt and 50 ml of THF, theresulting suspension is washed twice with a 5% solution of sodiumcarbonate, with water and with a saturated solution of NaCl and, afterdecantation, the solid in suspension is filtered off. The solid isdissolved in 400 ml of boiling THF and dried over sodium sulfate and thesolvent is partially evaporated off under vacuum. The crystallineproduct formed is filtered off to give 1.65 g of the expected product.M.p.=245°-248° C.

Preparation 78 3-5-(Benzyloxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) Benzyl 6-(tert-butoxycarbonylamino)hexanoate

1.94 ml of DBU and then 1.54 ml of benzyl bromide are added at RT to asolution of 3 g of 6-(tert-butoxycarbonylamino)hexanoic acid in 60 ml ofDCM and the mixture is stirred for 24 hours at RT. It is concentratedunder vacuum, the residue is taken up with 100 ml of water and extractedwith AcOEt, the organic phase is washed with a 5% solution of potassiumcarbonate, with a saturated solution of NaCl and with water and driedover sodium sulfate and the solvent is evaporated off under vacuum togive 2.8 g of the expected product, which is used as such.

B) 3-5-(Benzyloxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 4 g of the compound obtained in the previous step in 20 mlof DCM is cooled to +4° C., 40 ml of TFA are added and the mixture isstirred for 1 hour at +4° C. It is concentrated under vacuum, theresidue is taken up three times with 50 ml of DCM and the solvent isevaporated off under vacuum. The oil obtained is taken up with 30 ml ofchloroform, 4.5 g of the compound obtained in step C of Preparation 2are added, a solution of 5.24 ml of triethylamine in 5 ml of chloroformis then added dropwise and the mixture is stirred for 1 hour at RT. Itis concentrated under vacuum, the residue is extracted with AcOEt, theorganic phase is washed with a saturated solution of NaCl and with waterand dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using DCM and then aDCM/AcOEt mixture (90/10; v/v) as the eluent to give 3.8 g of theexpected product after crystallization from a DCM/hexane mixture.M.p.=98°-99° C.

The 1,3-dihydroindol-2-ones collected in TABLE I below are prepared byfollowing the procedures described in the Preparations above.

                                      TABLE I                                     __________________________________________________________________________     ##STR31##                                                                                                           Solvate                                                                       M.p. °C. or NMR                                                        cristallization                        Preparation                                                                         R'.sub.1                                                                          R'.sub.2                                                                          R.sub.3 R'.sub.4         solvent                                __________________________________________________________________________    79 (a)                                                                              5-Cl                                                                              H                                                                                  ##STR32##                                                                             ##STR33##       200 DCM/iso ether                      80 (b)                                                                              5-Cl                                                                              H                                                                                  ##STR34##                                                                             ##STR35##       238 DCM/iso ether                      81 (a)                                                                              5-Cl                                                                              H                                                                                  ##STR36##                                                                             ##STR37##       218 DCM/iso ether                      82 (c)                                                                              5-Cl                                                                              H                                                                                  ##STR38##                                                                             ##STR39##       165-168 DCM/iso ether                  83 (c)                                                                              5-Cl                                                                              H                                                                                  ##STR40##                                                                             ##STR41##       189-193 DCM/iso ether                  84 (c)                                                                              5-Cl                                                                              H                                                                                  ##STR42##                                                                             ##STR43##       0.33 H.sub.2 O 195-198 DCM/iso                                                ether                                  85 (a)                                                                              5-Cl                                                                              H                                                                                  ##STR44##                                                                            NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 OH                                                        0.5 H.sub.2 O 173-174 DCM/iso                                                 ether                                  86 (d)                                                                              5-Cl                                                                              H                                                                                  ##STR45##                                                                            NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 OSi(Me).sub.3                                             140-142 DCM/iso ether                  87 (a)                                                                              5-Cl                                                                              H                                                                                  ##STR46##                                                                            NH(CH.sub.2).sub.3 OMe                                                                         192                                    88 (a)                                                                              5-Cl                                                                              H                                                                                  ##STR47##                                                                             ##STR48##       159 DCM/iso ether                      89 (c)                                                                              5-Cl                                                                              H                                                                                  ##STR49##                                                                             ##STR50##       110 pentane                            90 (a)                                                                              5-Cl                                                                              H                                                                                  ##STR51##                                                                             ##STR52##       148 DCM/iso ether                      91 (b)                                                                              5-Cl                                                                              H                                                                                  ##STR53##                                                                             ##STR54##       190 iso ether                          92 (f)                                                                              5-Cl                                                                              H                                                                                  ##STR55##                                                                             ##STR56##       185 iso ether/hexane                   93 (g)                                                                              5-Cl                                                                              H                                                                                  ##STR57##                                                                            NH(CH.sub.2).sub.3 COOBz                                                                       used as such                           94 (o)                                                                              5-Cl                                                                              H                                                                                  ##STR58##                                                                            NH(CH.sub.2).sub.4 COOBz                                                                       116-117 DCM/iso ether                  95 (a)                                                                              5-Cl                                                                              H                                                                                  ##STR59##                                                                            NH(CH.sub.2).sub.5 CN                                                                          160-162 DCM/iso ether                  96 (b)                                                                              5-Cl                                                                              H                                                                                  ##STR60##                                                                             ##STR61##       251 DCM/iso ether                      97 (h)                                                                              5-Cl                                                                              H                                                                                  ##STR62##                                                                             ##STR63##       194-195 DCM/iso ether                  98 (i)                                                                              5-Cl                                                                              H                                                                                  ##STR64##                                                                             ##STR65##       120 DCM/iso ether                      99 (j)                                                                              5-Et                                                                              H                                                                                  ##STR66##                                                                            NHMe             139-140 DCM/iso ether                  100 (k)                                                                             5-Cl                                                                              6-Cl                                                                               ##STR67##                                                                            NH(CH.sub.2).sub.3 OMe                                                                         163-164 DCM/iso ether                  101 (l)                                                                             5-Cl                                                                              6-Cl                                                                               ##STR68##                                                                             ##STR69##       NMR oil                                102 (m)                                                                             5-Cl                                                                              6-Cl                                                                               ##STR70##                                                                             ##STR71##       130 DCM/iso ether                      103 (n)                                                                             5-Cl                                                                              6-Cl                                                                               ##STR72##                                                                            NH(CH.sub.2).sub.5 NHBoc                                                                       205-210 DCM/THF/ iso ether             104 (p)                                                                             5-Cl                                                                              4-Cl                                                                               ##STR73##                                                                             ##STR74##       238                                    105 (q)                                                                             5-Cl                                                                              6-Cl                                                                               ##STR75##                                                                             ##STR76##       173                                    106 (r)                                                                             5-Cl                                                                              6-Me                                                                               ##STR77##                                                                             ##STR78##       184 DCM/iso ether                      107 (s)                                                                             5-Cl                                                                              H                                                                                  ##STR79##                                                                             ##STR80##       195 iso ether                          108 (b)                                                                             5-Cl                                                                              H                                                                                  ##STR81##                                                                            NH(CH.sub.2).sub.2 SEt                                                                         128 DCM/iso ether                      109 (c)                                                                             5-Cl                                                                              H                                                                                  ##STR82##                                                                             ##STR83##       168-170 DCM/iso ether                  110 (t)                                                                             5-Cl                                                                              H                                                                                  ##STR84##                                                                             ##STR85##       96-98 DCM/iso ether                    111 (u)                                                                             5-Cl                                                                              H                                                                                  ##STR86##                                                                             ##STR87##       --                                     112 (v)                                                                             5-CF.sub.3                                                                        H                                                                                  ##STR88##                                                                            NHMe             153-155 DCM/iso ether                  113 (w)                                                                             5-OEt                                                                             H                                                                                  ##STR89##                                                                             ##STR90##       170-172 DCM/iso ether                  114 (x)                                                                             5-Cl                                                                              4-Me                                                                               ##STR91##                                                                             ##STR92##       --                                     115 (y)                                                                             5-Cl                                                                              6-Me                                                                               ##STR93##                                                                             ##STR94##       200-203 EtOH                           __________________________________________________________________________

(a) This compound is prepared according to the procedure described inPreparation 30 by using the appropriate amines.

(b) This compound is prepared according to the procedure described inPreparation 31 by using the appropriate amines in the presence of DIPEA.

(c) This compound is prepared according to the procedure described inPreparation 32 by using the appropriate amines.

(d) This compound is prepared according to the procedure described inPreparation 35 from the compound obtained in Preparation 85.

(e) This compound is prepared according to the procedure described inPreparation 39 by using the appropriate amines.

(f) This compound is prepared according to the procedure described instep C of Preparation 50 from the compound obtained in step B ofPreparation 50 and the appropriate amines.

(g) This compound is prepared according to the procedure described inPreparation 52.

(h) This compound is prepared according to the procedure described inPreparation 61 from the compound obtained in Preparation 2, bromoacetylbromide and diethylamine.

(i) This compound is prepared according to the procedure described instep B of Preparation 62 by using the appropriate amine.

(j) This compound is prepared according to the procedures described insteps A, B, C, D and then E of Preparation 65.

(k) This compound is prepared according to the procedure described instep E of Preparation 72 from the compound obtained in step C ofPreparation 72 and (3-methoxypropyl)amine in the presence oftriethylamine.

(l) This compound is prepared according to the procedure described instep E of Preparation 36 from the compound obtained in step C ofPreparation 72.

(m) This compound is prepared according to the procedure described inPreparation 38 from the compound obtained in step C of Preparation 72.

(n) This compound is prepared according to the procedure described instep D of Preparation 43 from the compound obtained in step C ofPreparation 72.

(o) This compound is prepared according to the procedure described instep B of Preparation 78.

(p) This compound is prepared according to the procedure described inPreparation 80 from3-bromo-4,5-dichloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one (m.p.=230° C.), itself obtained according to the procedure described in stepC of Preparation 72 from4,5-dichloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one, obtained as aby-product in step B of Preparation 72.

(q) This compound is prepared according to the procedure described inPreparation 80 from the compound obtained in step C of Preparation 72.

(r) This compound is prepared according to the procedure described inPreparation 80 from the compound obtained in step B' of Preparation 71.

(s) This compound is prepared according to the procedure described inPreparation 49 from the compound obtained in step C of Preparation 2 and1,3-diamino-2,2-dimethylpropane.

(t) the more polar isomer; this compound is prepared according to theprocedure described in step B of Preparation 59 from the compoundobtained in step C of Preparation 2 andN-ε-(benzyloxycarbonyl)-D-lysinol.

α_(D) ²⁵ =+99.2° C. (c=0.275; chloroform).

(u) This compound is prepared according to the procedure described inPreparation 60 from the compound obtained in Preparation 110 and is usedas such in EXAMPLE 269.

(v) This compound is prepared according to the procedures described insteps A, B, C and then D of Preparation 69.

(w) This compound is prepared according to the procedure described inPreparation 68 from the compound obtained in Preparation 16 andacetaldehyde.

(x) This compound is prepared according to the procedure described inPreparation 63 from3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-4-methylindol-2-oneitself obtained according to the procedure described in step C ofPreparation 70, by using ammonia gas.

(y) this compound is prepared according to the procedure described inPreparation 63 from3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-6-methylindol-2-one,itself obtained according to the procedure described in step C ofPreparation 70, by using ammonia gas.

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of Preparation 101

2.1 ppm:s:6H

2.35 ppm:t:2H

2.5 ppm:mt:2H

3.0 ppm:t:1H

3.4 ppm:t:4H

6.8 to 8.2 ppm:m:6H

10.95 ppm:s:1H

Preparations of compounds of formula (III) or (IV) Preparation 1164-(N',N'-Diethylureido)benzenesulfonyl chloride A)N',N'-Diethyl-N-phenylurea

A solution of 10 g of aniline in 50 ml of pyridine is cooled to 0° C.and a solution of 14.56 g of diethylcarbamoyl chloride in 10 ml ofpyridine is added slowly. The mixture is stirred for 6 hours, thetemperature being allowed to rise to RT, and is then poured into water.It is extracted with AcOEt, washed with water and with a 5% solution ofpotassium hydrogensulfate, dried over sodium sulfate and evaporatedunder vacuum. The residue is chromatographed on silica using DCM andthen a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 13 g of theexpected product, which is used as such in the next step.

B) 4-(N',N'-Diethylureido)benzenesulfonyl chloride

3.5 ml of chlorosulfonic acid are cooled to +5° C. and 2 g of thecompound obtained in the previous step are added in 15 minutes. Thereaction mixture is heated at 60° C. for 2 hours, with vigorousstirring, and then cooled to RT. Ice and then water are added slowly andthe mixture is extracted with AcOEt, washed with water to pH 7, driedover sodium sulfate and evaporated under vacuum to give the expectedproduct after recrystallization from benzene. m=1.54 g. M.p.=148°-150°C.

Preparation 117 tert-Butyl 4-bromomethylbenzoate A) tert-Butyl4-methylbenzoate

37 g of tert-butanol and then 26 ml of pyridine are added to 39.04 g ofp-toluoyl chloride and the reaction mixture is refluxed for 3 hours.After cooling, it is poured into water, extracted with AcOEt, washedwith a 1N solution of HCl and then with a 5% solution of sodiumhydrogencarbonate, dried over sodium sulfate and evaporated undervacuum. The residue is chromatographed on silica using hexane and then ahexane/DCM mixture (80/20; v/v) as the eluent to give 38.9 g of theexpected product, which is used as such in the next step.

B) tert-Butyl 4-bromomethylbenzoate

A mixture of 10.4 g of the compound obtained in the previous step, 9.64g of N-bromosuccinimide, 0.10 g of dibenzoyl peroxide and 250 ml of CCl₄is refluxed for 40 minutes. After cooling, the insoluble material isfiltered off and the filtrate is taken up with CCl₄, washed with a 5%solution of sodium hydrogencarbonate, dried over sodium sulfate andevaporated under vacuum to give 13 g of a clear oil, which issubsequently used as such.

Preparation 118 1-Acetylindoline-5-sulfonyl chloride A) 1-Acetylindoline

A solution of 11.9 g of indoline in 100 ml of chloroform is cooled to 0°C. 13.9 ml of triethylamine are added and a solution of 10.4 ml ofacetic anhydride in 10 ml of chloroform is then added dropwise, followedby 0.1 g of 4-dimethylaminopyridine. After stirring for two hours at RT,water is added to the reaction mixture, extraction is carried out withchloroform, the organic phase is dried over sodium sulfate and thesolvent is evaporated off under vacuum to give 15.44 g of the expectedproduct, which is used as such.

B) l-Acetylindoline-5-sulfonyl chloride

32 ml of chlorosulfonic acid are cooled to +5° C. and 15.4 g of thecompound obtained in the previous step are added rapidly in portions.The reaction mixture is heated at 60° C. for 2 hours and then cooled toRT. Ice is added slowly and the precipitate formed is filtered off togive 18.07 g of the expected product after crystallization from aDCM/iso ether mixture.

NMR spectrum at 200 MHz in DMSO-d₆

2.15 ppm:s:3H

3.1 ppm:t:2H

4.1 ppm:t:2H

7.3 to 8.1 ppm:m:3H

Preparation 119 1-(Methoxycarbonyl)indoline-5-sulfonyl chloride A)l-Methoxycarbonylindoline

A solution of 10 g of indoline in 10 ml of pyridine is cooled to 0° C. asolution of 7.9 g of methyl chloroformate in 10 ml of DCM is addeddropwise and the mixture is stirred for 1 hour at 0C. A further solutionof 7.9 g of methyl chloroformate in 10 ml of DCM is then added and thereaction mixture is concentrated under vacuum. The residue is taken upwith water and extracted with AcOEt, the organic phase is washed with a5% solution of potassium hydrogensulfate, with water and with asaturated solution of NaCl and dried over sodium sulfate and the solventis evaporated off under vacuum to give 8.3 g of the expected productafter trituration in a DCM/iso ether mixture and then filtration.M.p.=69°-70° C.

B) 1-(Methoxycarbonyl)indoline-5-sulfonyl chloride

A mixture of 3 g of the compound obtained in the previous step and 7 mlof chlorosulfonic acid is stirred for 90 minutes at RT. Ice and thenwater are successively added to the reaction mixture, extraction iscarried out with AcOEt, the organic phase is washed with water to pH 7and dried over sodium sulfate and the solvent is evaporated off undervacuum to give 2.8 g of the expected product after crystallization froma DCM/iso ether mixture. M.p.=113°-114° C.

Preparation 120 1-(Diethylaminocarbonyl)indoline-5-sulfonyl chloride A)1-(Diethylaminocarbonyl)indoline

A solution of 6 g of indoline in 10 ml of pyridine is cooled to 0° C.6.4 ml of diethylcarbamoyl chloride are added dropwise and the mixtureis stirred for 18 hours at RT. Water is added to the reaction mixture,extraction is carried out with AcOEt, the organic phase is washed withwater and with a 5% solution of potassium hydrogensulfate and dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using DCM as the eluent to give 8 gof the expected product, which is used as such.

B) 1-(Diethylaminocarbonyl)indoline-5-sulfonyl chloride

12.3 ml of chlorosulfonic acid are cooled to +5° C. and 8 g of thecompound obtained in the previous step are added rapidly. The reactionmixture is heated at 60° C. for 2 hours, with vigorous stirring, andthen cooled to RT. Ice and then water are added slowly, extraction iscarried out with AcOEt, the organic phase is washed with water to pH 7and dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a DCM/ AcOEtmixture (95/5; v/v) as the eluent to give 4.54 g of the expectedproduct.

NMR spectrum at 200 MHz in DMSO-d₆

1.15 ppm:t:6H

2.95 ppm:t:2H

3.2 ppm:qd:4H

3.75 ppm:t:2H

6.7 to 7.5 ppm:m:3H

EXAMPLE 13-Amino-5-chloro-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-phenylindol-2-one

A solution of 0.3 g of 3-amino-5-chloro-1,3-dihydro-3-phenylindol-2-onein 7 ml of DMF is cooled to 0C under an argon atmosphere and 0.037 g ofsodium hydride as an 80% dispersion in oil is added. After stirring for20 minutes, 0.275 g of 2,4-dimethoxybenzenefulfonyl chloride is addedand the reaction mixture is stirred overnight, the temperature beingallowed to rise to RT. It is poured into water, extracted with AcOEt,washed with water and with a saturated solution of NaCl, dried oversodium sulfate and evaporated under vacuum. The residue ischromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as theeluent to give the expected product after crystallization from a DCM/isoether/hexane mixture. m=0.31 g. M.p.=108-110° C.

EXAMPLE 23-Acetamido-5-chloro-1,3-dihydro-1-(2,4-di-methoxybenzenesulfonyl)-3-phenylindol-2-one

0.051 g of triethylamine and then 0.04 g of acetyl chloride are added toa solution of 0.234 g of the compound obtained in EXAMPLE 1 in 2 ml ofDCM and the reaction mixture is stirred for two hours at RT. It ispoured into water, extracted with DCM, washed with water, dried oversodium sulfate and evaporated under vacuum to give the expected productafter crystallization and recrystallization from a DCM/iso ether/ MeOHmixture. m=0.146 g. M.p.=253° C.

EXAMPLE 33-Amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.315 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

0.256 g of 2,4-dimethoxybenzenesulfonyl chloride. This gives theexpected product after crystallization from a DCM/iso ether mixture.m=0.300 g. M.p.=179-180° C. EXAMPLE 45-Chloro-3-(ethanecarboxamido)-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)indol-2-one

0.08 g of propionyl chloride is added to a solution of 0.33 g of thecompound obtained in EXAMPLE 3 in 3 ml of pyridine and the reactionmixture is stirred for 1 hour at RT. It is poured into water, extractedwith AcOEt, dried over sodium sulfate and evaporated under vacuum. Theresidue is chromatographed on silica using a DCM/AcOEt mixture (98/2;v/v) as the eluent to give the expected product after crystallizationfrom a DCM/iso ether mixture. m=0.18 g. M.p.=188° C.

EXAMPLE 55-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-(methoxycarboxamido)indol-2-one

0.066 g of pyridine and then 0.095 g of methyl chloroformate are addedat RT to a solution of 0.205 g of the compound obtained in EXAMPLE 3 in2 ml of DCM. The reaction mixture is stirred for 72 hours at between 0°and +4° C. and poured into water. It is extracted with DCM, washed witha 5% solution of potassium hydrogensulfate and with water, dried oversodium sulfate and evaporated under vacuum to give the expected productafter crystallization from a DCM/iso ether mixture. m=0.175 g.M.p.=225°-228° C.

EXAMPLE 65-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-(methylsulfonamido)indol-2-one

A solution of 0.4 g of the compound obtained in EXAMPLE 3 in 5 ml ofpyridine is cooled to 0° C. and 0.1 g of methanesulfonyl chloride isadded. The mixture is stirred for 18 hours, the temperature beingallowed to rise to RT, and evaporated under vacuum. The residue isextracted with AcOEt, washed with a 5% solution of potassiumhydrogensulfate, dried over sodium sulfate and evaporated under vacuum.The residue due is chromatographed on silica using a DCM/AcOEt mixture(98/2; v/v) as the eluent to give the expected product aftercrystallization from a DCM/iso ether mixture. m=0.22 g. M.p.=252° C.

EXAMPLE 75-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-(phenoxycarboxamido)indol-2-one

0.250 g of phenyl chloroformate is added at RT to a solution of 0.530 gof the compound obtained in EXAMPLE 3 in 4 ml of pyridine. The mixtureis stirred for 18 hours at RT and evaporated under vacuum. The residueis extracted with DCM, washed with a 5% solution of potassiumhydrogensulfate and with water, dried over sodium sulfate and evaporatedunder vacuum. The residue is chromatographed on silica using a DCM/AcOEtmixture (98/2; v/v) as the eluent to give the expected product aftercrystallization from a DCM/iso ether mixture. m=0.47 g. M.p.=95°-100° C.

EXAMPLE 85-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-ureidoindol-2-one

1 ml of concentrated aqueous ammonia is added at RT to a solution of0.400 g of the compound obtained in EXAMPLE 7 in 6 ml of EtOH and thereaction mixture is stirred for 18 hours. It is evaporated under vacuumand the residue is taken up with AcOEt, washed with water and dried oversodium sulfate. After evaporation under vacuum, the residue ischromatographed on silica using a DCM/AcOEt mixture (50/50; v/v) as theeluent to give the expected product after crystallization from a DCM/isoether mixture. m=0.15 g. M.p.=285° C.

EXAMPLE 95-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-(N',N'-dimethylureido)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 8 from 0.400 g of the compound obtained in EXAMPLE 7 and 0.3 mlof a 33% solution of dimethylamine in EtOH. The expected product isobtained after crystallization from a DCM/iso ether mixture. m=0.30 g.M.p.=246° C.

EXAMPLE 105-Chloro-3-(2-chlorophenyl)-3-(N',N'-diethylureido)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-indol-2-one

A mixture of 0.460 g of the compound obtained in EXAMPLE 7, 0.082 g ofdiethylamine, 4 ml of chloroform and 4 ml of EtOH is heated at 60° C.for 18 hours. The reaction mixture is evaporated under vacuum and theresidue is chromatographed on silica using a DCM/AcOEt mixture (95/5;v/v) as the eluent to give the expected product after crystallizationfrom a DCM/iso ether mixture. m=0.20 g. M.p.=222° C.

EXAMPLE 113-Amino-5-chloro-3-(2-chlorophenyl)-1,3-di-hydro-1-(4-nitrobenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 10 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 7.55 g of4-nitrobenzenesulfonyl chloride. The expected product is obtained aftercrystallization from a DCM/iso ether mixture. m=14 g. M.p.=202° C.

EXAMPLE 125-Chloro-3-(2-chlorophenyl)-3-(N',N'-diethylureido)-1,3-dihydro-1-(4-nitrobenzenesulfonyl)indol-2-one

A)5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(4-nitro-benzenesulfonyl)-3-(phenoxycarboxamido)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 7 from 11 g of the compound obtained in EXAMPLE 11 and 4.63 g ofphenyl chloroformate. Chromatography on silica using DCM as the eluentgives 12.3 g of the expected product, which is used as such in the nextstep.

B)5-Chloro-3-(2-chlorophenyl)-3-(N',N'-diethylureido)-1,3-dihydro-1-(4-nitrobenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 10 from 10 g of the compound obtained in the previous step and1.9 g of diethylamine. The expected product is obtained aftercrystallization from a DCM/iso ether mixture. m=7.7 g. M.p.=185° C.

EXAMPLE 131-(4-Aminobenzenesulfonyl)-5-chloro-3-(2-chlorophenyl)-3-(N',N'-diethylureido)-1,3-dihydroindol-2-one

7.6 g of the compound obtained in EXAMPLE 12 in 100 ml of EtOH and 50 mlof THF are reduced with hydrogen under a pressure of 50 bar for 6 hoursat RT, in the presence of 2 g of Raney nickel. The mixture is filteredon Celite and the filtrate is evaporated under vacuum. The residue ischromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as theeluent to give the expected product after crystallization from a DCM/iso ether mixture. m=3.2 g. M.p.=210° C.

EXAMPLE 14 1-4-(tert-Butanecarboxamido)benzenesulfonyl!-5-chloro-3-(2-chlorophenyl)-3-(N',N'-diethylureido)-1,3-dihydroindol-2-one

A solution of 0.400 g of the compound obtained in EXAMPLE 13 in 3 ml ofpyridine is cooled to 0° C. and 0.100 g of pivaloyl chloride is added.The mixture is stirred for 18 hours, the temperature being allowed torise to RT, and then evaporated under vacuum. The residue is extractedwith AcOEt, washed with a 5% solution of potassium hydrogensulfate,dried over sodium sulfate and evaporated under vacuum. The residue ischromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as theeluent to give the expected product after crystallization from a DCM/isoether mixture. m=0.180 g. M.p.=228° C.

EXAMPLE 15 5-Chloro-3-(2-chlorophenyl)-3-(N', N'-diethylureido)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one A)5-Chloro-3-(2-chlorophenyl)-3-(N',N'-diethylureido)-1,3-dihydro-1-4-(phenoxycarboxamido)benzenesulfonyl!indol-2-one

A solution of 0.500 g of the compound obtained in EXAMPLE 13 in 10 ml ofpyridine is cooled to 0°-5° C. and 0.156 g of phenyl chloroformate isadded. The mixture is stirred for 18 hours, the temperature beingallowed to rise to RT, and then evaporated under vacuum. The residue isextracted with AcOEt, washed with a 5% solution of potassiumhydrogensulfate, dried over sodium sulfate and evaporated under vacuum.The residue is chromatographed on silica using an AcOEt/ hexane mixture(30/70; v/v) as the eluent to give 0.53 g of the expected product, whichis used as such in the next step.

B) 5-Chloro-3-(2-chlorophenyl)-3-(N',N'-diethylureido)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 10 from 0.53 g of the compound obtained in the previous step and0.136 g of diethylamine. The expected product is obtained aftercrystallization from a DCM/iso ether mixture. m=0.24 g. M.p.=200° C.

EXAMPLE 163-Amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 7 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 6 g of2-methoxy-4-nitrobenzenesulfonyl chloride. The expected product isobtained after crystallization from a DCM/iso ether/THF mixture. m=9.4g. M.p.=229° C.

EXAMPLE 173-Amino-1-(4-amino-2-methoxybenzenesulfonyl)-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

2.17 g of the compound obtained in EXAMPLE 16 in 30 ml of MeOH and 30 mlof THF are reduced with hydrogen under a pressure of 40 bar for 4 hoursat RT, in the presence of 1 g of Raney nickel. The mixture is filteredon Celite and the filtrate is evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (90/10;v/v) as the eluent to give the expected product after crystallizationfrom a DCM/iso ether mixture. m=1.3 g. M.p.=198° C.

EXAMPLE 18 and EXAMPLE 19 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-2-methoxy-4-(phenoxycarboxamido)benzenesulfonly!-3-(phenoxycarboxamido)indol-2-one(EXAMPLE 18) and 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl!indol-2-one (EXAMPLE 19)

These compounds are prepared according to the procedure described inEXAMPLE 7 from 1.15 g of the compound obtained in EXAMPLE 17 and 0.32 mlof phenyl chloroformate. The product is chromatographed on silica usingDCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluent. Twocompounds are separated out:

the less polar isomer: compound of EXAMPLE 18. m=0.610 g.

the more polar isomer: compound of EXAMPLE 19. m=0.406 g.

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 18

3.45 ppm:s:3H

6.6 to 8.0 ppm:m:20H

9.3 ppm:s:1H

10.8 ppm:s: 1H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 19

3.1 ppm:s:2H

3.6 ppm:s:3H

6.6 to 8.3 ppm:m:15H

10.8 ppm:s:1H

EXAMPLE 20 5-Chloro-3-(2-chlorophenyl)-3-(N',N'-diethylureido)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 10 from 0.610 g of the compound obtained in EXAMPLE 18 and 0.248g of diethylamine. Chromatography on silica using a gradient of aDCM/AcOEt mixture (from 95/5; v/v to 80/20; v/v) as the eluent gives theexpected product after crystallization from a DCM/iso ether mixture.m=0.456 g. M.p.=185°-190° C.

EXAMPLE 21 3-Amino-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydroindol-2-one

A mixture of 0.406 g of the compound obtained in EXAMPLE 19, 0.100 g ofdiethylamine and 5 ml of chloroform is heated at 600° C. for 4 hours. Itis evaporated under vacuum and the residue is chromatographed on silicausing DCM and then a DCM/AcOEt mixture (90/10; v/v) as the eluent togive the expected product after crystallization from a DCM/iso ethermixture. m=0.280 g. M.p.=152°-158° C.

EXAMPLE 225-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methoxycarboxamido)-1-(2-methoxy-4-nitrobenzenesulfonyl)indol-2-one

A solution of 2.8 g of the compound obtained in EXAMPLE 16 in 15 ml ofpyridine is cooled in an ice bath and a solution of 0.85 ml of methylchloroformate in 3 ml of DCM is added. The reaction medium is stirredfor 3 days at RT and poured into water. It is extracted with AcOEt,washed with water, with a 1N solution of HCl and with water, dried oversodium sulfate and evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (90/10;v/v) as the eluent to give 0.800 g of the expected product.

NMR spectrum at 200 MHz in DMSO-d₆

3.4 ppm:s:3H

3.7 ppm:s:3H

7.1 to 8.3 ppm:m:10H 8.75 ppm:s:1H

EXAMPLE 231-(4-Amino-2-methoxybenzenesulfonyl)-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methoxycarboxamido)-indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 17 from 0.800 g of the compound obtained in EXAMPLE 22. Afterfiltration on Celite, the filtrate is evaporated under vacuum to give0.742 g of the expected product.

NMR spectrum at 200 MHz in DMSO-d₆

3.45 ppm:s:3H

3.55 ppm:s:3H

6.0 to 8.0 ppm:m:10H and 2H

8.65 ppm:s:1H

EXAMPLE 24 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(methoxycarboxamido)indol-2-oneA) 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methoxycarboxamido)-1-2-methoxy-4-(phenoxycarboxamido)-benzenesulfonly!indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 7 from 0.742 g of the compound obtained in EXAMPLE 23 and 0.18ml of phenyl chloroformate. Chromatography on silica using a gradient ofa DCM/AcOEt mixture (from 95/5; v/v to 80/20; v/v) as the eluent gives0.905 g of the expected product, which is used as such in the next step.

B) 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(methoxycarboxamido)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 10 from 0.100 g of the compound obtained in the previous stepand 0.022 g of diethylamine. The expected product is obtained aftercrystallization from a hot EtOH/DMF mixture. m=0.050 g. M.p.=240°-245°C.

EXAMPLE 253-Acetamido-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)indol-2-one

A solution of 2.8 g of the compound obtained in EXAMPLE 16 in 10 ml ofpyridine is cooled in an ice bath and 0.51 ml of acetyl chloride isadded. The reaction medium is stirred for 3 hours at RT and poured intowater. It is extracted with AcOEt, washed with water and with a 5%solution of potassium hydrogensulfate, dried over sodium sulfate andevaporated under vacuum. The residue is taken up with DCM and theprecipitate formed is filtered off to give 2.8 g of the expectedproduct, a sample of which is crystallized from an MeOH/iso ethermixture. M.p.=205°-210° C.

EXAMPLE 263-Acetamido-1-(4-amino-2-methoxybenzenesulfonyl)-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 17 from 2.17 g of the compound obtained in EXAMPLE 25. Afterfiltration on Celite and evaporation of the filtrate under vacuum, theresidue is taken up with DCM and the precipitate formed is filtered off,washed with iso ether and dried in an oven at 90° C. to give 1.53 g ofthe expected product.

NMR spectrum at 200 MHz in DMSO-d₆

1.8 ppm:s:3H

3.35 ppm:s:3H

5.9 to 7.9 ppm:m:10H and 2H

9.0 ppm:s:1H

EXAMPLE 27 3-Acetamido-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydroindol-2-oneA) 3-Acetamido-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl!-indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 7 from 1.53 g of the compound obtained in EXAMPLE 26. Dryingover sodium sulfate and evaporation under vacuum gives 1.60 g of theexpected product, which is used as such in the next step.

B) 3-Acetamido-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 10 from 0.300 g of the compound obtained in the previous stepand 0.068 g of diethylamine. The expected product is obtained aftercrystallization from a DCM/iso ether mixture. m=0.160 g. M.p.=180°-185°C.

EXAMPLE 28 3-Acetamido-1-4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) Benzyl 4-3-amino-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!sulfonyl-3-methoxybenzoate

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.860 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1 g ofbenzyl 4-chlorosulfonylate3-methoxybenzoate. Chromatography on silicausing a DCM/AcOEt mixture (99/1; v/v) as the eluent gives 1.38 g of theexpected product, which is used as such in the next step.

B) Benzyl 4-3-acetamido-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!sulfonyl-3-methoxybenzoate

A solution of 0.600 g of the compound obtained in the previous step in 4ml of pyridine is cooled to 0° C. and a solution of 0.102 g of acetylchloride in 2 ml of DCM is added. The reaction mixture is stirred for 30minutes and poured into water. It is extracted with AcOEt, washed with a5% solution of potassium hydrogensulfate, dried over sodium sulfate andevaporated under vacuum. The residue is chromatographed on silica usinga DCM/AcOEt mixture (90/10; v/v) as the eluent to give the expectedproduct after crystallization from a DCM/iso ether mixture. m=0.466 g.M.p.=177° C.

C) 4-3-Acetamido-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!sulfonyl-3-methoxybenzoicacid

A mixture of 0.400 g of the compound obtained in the previous step,0.040 g of 10% palladium-on-charcoal and 15 ml of ACOH is hydrogenolyzedat atmospheric pressure for 30 minutes at RT. It is filtered on Celiteand the filtrate is evaporated under vacuum. The residue is taken upwith ether and the precipitate formed is filtered off to give 0.310 g ofthe expected product, which is used as such in the next step.

D) 3-Acetamido-1-4-(N-tert-butylcarbamoyl)-2-methoxy-benzenesulfonyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 0.310 g of the compound obtained in the previous step in 8ml of DMF is cooled to 0° C. and 0.074 g of DIPEA and then 0.269 g ofBOP are added. After stirring for 15 minutes, 0.055 g of tert-butylamineis added and the mixture is stirred for 6 hours, the temperature beingallowed to rise to RT. It is evaporated under vacuum and the residue istaken up with water, extracted with AcOEt, washed with a 5% solution ofpotassium hydrogensulfate and with water, dried over sodium sulfate andevaporated under vacuum. The residue is chromatographed on silica usinga DCM/ AcOEt mixture (80/20; v/v) as the eluent to give the expectedproduct after crystallization from a DCM/iso ether mixture. m=0.15 g.M.p.=265° C.

EXAMPLE 29 3-Amino-1-4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) 4-3-Amino-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!sulfonyl-3-methoxybenzoicacid

This compound is prepared according to the procedure described in step Cof EXAMPLE 28 from 0.700 g of the compound obtained in step A of EXAMPLE28. After filtration on Celite and evaporation of the filtrate undervacuum, the residue is taken up with iso ether. Filtration gives 0.530 gof the expected product, which is used as such in the next step.

B) 3-Amino-1-4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 0.530 g of the compound obtained in the previous step,0.134 g of DIPEA, 0.228 g of tert-butylamine and 6 ml of DMF is cooledto 0° C. and 0.483 g of BOP is added gradually. The mixture is stirredfor 18 hours, the temperature being allowed to rise to RT. Water isadded to the reaction medium, extraction is carried out with AcOEt andthe extract is dried over sodium sulfate and evaporated under vacuum.The residue is chromatographed on silica using a DCM/ AcOEt mixture(95/5; v/v) as the eluent to give the expected product aftercrystallization from iso ether. m=0.150 g. M.p.=263°-265° C.

EXAMPLE 30 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-(dimethylamino)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.500 g of5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one and0.453 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride.Chromatography on silica using a gradient of a hexane/AcOEt mixture(80/20; v/v to 60/40; v/v) as the eluent gives the expected productafter crystallization from a DCM/iso ether mixture. m=0.520 g.M.p.=146°-150° C.

EXAMPLE 31 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethyl-N-methylureido)benzenesulfonyl!-1,3-dihydro-3-(dimethylamino)indol-2-one

A solution of 0.420 g of the compound obtained in EXAMPLE 30 in 7 ml ofDMF is cooled to 0° C. under an argon atmosphere and 0.027 g of sodiumhydride as an 80% dispersion in oil is added. After stirring for 30minutes, 0.05 ml of methyl iodide is added and the reaction mixture isstirred for 10 minutes. It is poured into water, extracted with AcOEt,washed with water, dried over sodium sulfate and evaporated undervacuum. The residue is chromatographed on silica using DCM and then aDCM/AcOEt mixture (95/5; v/v) as the eluent to give the expected productafter crystallization from a DCM/iso ether mixture. m=0.211 g.M.p.=145°-148° C.

EXAMPLE 32 3-Amino-5-chloro-1-4-(N',N'-diethylureido)-benzenesulfonyl!-1,3-dihydro-3-(2-methoxyphenyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.266 g of3-amino-5-chloro-1,3-dihydro-3-(2-methoxyphenyl)indol-2-one and 0.280 gof 4-(N',N'-diethylureido)benzenesulfonyl chloride. The expected productis obtained after crystallization from a DCM/iso ether mixture. m=0.160g. M.p.=214°-217° C.

EXAMPLE 335-Chloro-3-(2-chlorophenyl)-1-(4-ethylamino-2-methoxybenzenesulfonyl)-1,3-dihydro-3-(methoxycarboxamido)indol-2-one

2 ml of AcOH and then 0.15 ml of acetaldehyde are added at RT to asolution of 0.750 g of the compound obtained in EXAMPLE 23 in 17 ml ofMeOH and 5 ml of THF, and 0.108 g of sodium cyanoborohydride is added in10 minutes. As the reaction is immediate, 2 drops of concentrated HClare added and the reaction medium is then neutralized by the addition ofa 5% solution of potassium carbonate. The solvents are evaporated offunder vacuum and the residue is extracted with AcOEt, washed with water,dried over sodium sulfate and evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (97/3;v/v) as the eluent to give the expected product after crystallizationfrom a DCM/iso ether mixture. m=0.435 g. M.p.=192°-195° C.

EXAMPLE 345-Chloro-3-(2-chlorophenyl)-1-(4-diethylamino-2-methoxybenzenesulfonyl)-1,3-dihydro-3-(methoxycarboxamido)indol-2-one

0.8 ml of AcOH and then 0.12 ml of acetaldehyde are added at RT to asolution of 0.311 g of the compound obtained in EXAMPLE 33 in 7 ml ofMeOH and 2 ml of THF. 0.086 g of sodium cyanoborohydride is then addedin 3 portions in 4 days. When the reaction has ended, 2 drops ofconcentrated HCl are added and the reaction medium is then neutralizedby the addition of a 5% solution of potassium carbonate. The solventsare evaporated off under vacuum and the residue is extracted with AcOEt,washed with water, dried over sodium sulfate and evaporated undervacuum. The residue is chromatographed on silica using DCM and then aDCM/ AcOEt mixture (95/5; v/v) as the eluent to give the expectedproduct after crystallization from a DCM/iso ether mixture. m=0.140 g.M.p.=210°-215° C.

EXAMPLE 35 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-(1S)-1-(methoxycarbonyl)ethylamino!indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.639 g of the compound obtained in Preparation 12(isomer A) and 0.490 g of 4-(N',N'-diethylureido)benzenesulfonylchloride. Chromatography on silica using a DCM/AcOEt mixture (95/5; v/v)as the eluent gives the expected product after crystallization from aDCM/iso ether mixture. m=0.350 g. M.p.=204° C. α_(D) ²⁰ =+114.5°(c=0.22; chloroform).

EXAMPLE 36 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-(1S)-1-(methoxycarbonyl)ethylamino!indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.392 g of the compound obtained in Preparation 13(isomer B) and 0.329 g of 4-(N',N'-diethylureido)benzenesulfonylchloride. Chromatography on silica using a DCM/AcOEt mixture (95/5; v/v)as the eluent gives the expected product after crystallization from aDCM/iso ether/ hexane mixture. m=0.225 g. M.p.=204° C. α_(D) ²⁰ =-139.4°(c=0.19; chloroform).

The compounds according to the invention collected in TABLE II below areprepared from the 1,3-dihydroindol-2-ones described in the Preparationsby following the procedures described in the Examples above.

                                      TABLE II                                    __________________________________________________________________________     ##STR95##                                                                                                               M.p. °C. or NMR                                                        cristallization                    Example                                                                            R.sub.3  R.sub.4     R.sub.5                                                                           R.sub.6      solvent                            __________________________________________________________________________    37 (a)                                                                              ##STR96##                                                                             NH.sub.2    3-OMe                                                                             4-OMe        150 DCM/iso ether                  38 (a)                                                                              ##STR97##                                                                             NH.sub.2    3-OMe                                                                             4-OMe        161 DCM/iso ether                  39 (a)                                                                              ##STR98##                                                                             NHMe        2-OMe                                                                             4-OMe        205 DCM/iso ether                  40 (a)                                                                              ##STR99##                                                                             NHMe        3-OMe                                                                             4-OMe        182 DCM/iso ether                  41 (b)                                                                              ##STR100##                                                                            NHMe        2-OMe                                                                             4-NO.sub.2   145 DCM/iso ether                  42 (c)                                                                              ##STR101##                                                                            NHMe        2-OMe                                                                             4-NH.sub.2   --                                 43 (d) et (m)                                                                       ##STR102##                                                                            NHMe        2-OMe                                                                              ##STR103##  208-210 DCM/iso ether              44 (f)                                                                              ##STR104##                                                                            NHMe        H                                                                                  ##STR105##  232 DCM/iso ether                  45 (f)                                                                              ##STR106##                                                                            NHCH.sub.2 Me                                                                             H                                                                                  ##STR107##  224-229 DCM/iso ether              46 (f)                                                                              ##STR108##                                                                            NHCH.sub.2 CH.sub.2 Me                                                                    H                                                                                  ##STR109##  160-164 DCM/iso ether              47 (f)                                                                              ##STR110##                                                                            NH(CH.sub.2).sub.4 Me                                                                     H                                                                                  ##STR111##  219-221 DCM/iso ether              48 (f)                                                                              ##STR112##                                                                             ##STR113## H                                                                                  ##STR114##  220-223 DCM/iso ether              49 (f)                                                                              ##STR115##                                                                             ##STR116## H                                                                                  ##STR117##  177 DCM/iso ether                  50 (f)                                                                              ##STR118##                                                                             ##STR119## H                                                                                  ##STR120##  246-248 DCM/iso ether              51 (a)                                                                              ##STR121##                                                                             ##STR122## 2-OMe                                                                             4-OMe        215-217 DCM/iso ether              52 (a)                                                                              ##STR123##                                                                             ##STR124## 3-OMe                                                                             4-OMe        168-170 DCM/iso ether              53 (g)                                                                              ##STR125##                                                                             ##STR126## H   4-NO.sub.2   245-247 DCM/iso ether              54 (h)                                                                              ##STR127##                                                                             ##STR128## H   4-NH.sub.2   NMR                                55 (b)                                                                              ##STR129##                                                                             ##STR130## 2-OMe                                                                             4-NO.sub.2   NMR                                56 (c)                                                                              ##STR131##                                                                             ##STR132## 2-OMe                                                                             4-NH.sub.2   155-158 DCM/hexane                 57 (d) et (m)                                                                       ##STR133##                                                                             ##STR134## 2-OMe                                                                              ##STR135##  205-210 DCM/iso ether              58 (a)                                                                              ##STR136##                                                                             ##STR137## 2-OMe                                                                             4-OMe        180-185 DCM/iso ether              59 (g)                                                                              ##STR138##                                                                             ##STR139## H   4-NO.sub.2   198-205 DCM/iso ether              60 (h)                                                                              ##STR140##                                                                             ##STR141## H   4-NH.sub.2   205-208 DCM/iso ether              61 (n)                                                                              ##STR142##                                                                             ##STR143## H                                                                                  ##STR144##  176-180 DCM/iso ether              62 (f)                                                                              ##STR145##                                                                            NHCH.sub.2 CH.sub.2 OMe                                                                   H                                                                                  ##STR146##  149-151 DCM/iso ether              63 (f)                                                                              ##STR147##                                                                             ##STR148## H                                                                                  ##STR149##  165 DCM/iso ether                  64 (a)                                                                              ##STR150##                                                                            NHCH.sub.2 CO.sub.2 Et                                                                    2-OMe                                                                             4-OMe        178 DCM/iso ether                  65 (a)                                                                              ##STR151##                                                                             ##STR152## 2-OMe                                                                             4-OMe        244 DCM/iso ether                  66 (i)                                                                              ##STR153##                                                                            NHCOMe      2-OMe                                                                             4-OMe        220-223 DCM/iso ether              67 (i)                                                                              ##STR154##                                                                            NHCOisoBu   2-OMe                                                                             4-OMe        255 DCM/iso ether                  68 (i)                                                                              ##STR155##                                                                             ##STR156## 2-OMe                                                                             4-OMe        260 DCM/iso ether                  69 (j)                                                                              ##STR157##                                                                            NHCOOEt     2-OMe                                                                             4-OMe        199 DCM/iso ether                  70 (j)                                                                              ##STR158##                                                                            NHCOOisoBu  2-OMe                                                                             4-OMe        299 DCM/iso ether                  71 (k)                                                                              ##STR159##                                                                             ##STR160## H                                                                                  ##STR161##  188 DCM/iso ether                  72 (e)                                                                              ##STR162##                                                                             ##STR163## 2-OMe                                                                             4-OMe        180 DCM/iso ether                  73 (e)                                                                              ##STR164##                                                                             ##STR165## 2-OMe                                                                             4-OMe        NMR DCM/iso ether                  74 (d) et (m)                                                                       ##STR166##                                                                            NHCOMe      2-OMe                                                                              ##STR167##  190-200 DCM/iso ether              75 (d) et (m)                                                                       ##STR168##                                                                            NHCOMe      2-OMe                                                                              ##STR169##  190-200 DCM/iso ether              76 (d) et (m)                                                                       ##STR170##                                                                            NHCOMe      2-OMe                                                                              ##STR171##  255-260 DCM/iso ether              77 (a)                                                                              ##STR172##                                                                            N.sub.3     2-OMe                                                                             4-OMe        122-125 DCM/iso ether              78 (b)                                                                              ##STR173##                                                                            NH.sub.2    2-OMe                                                                             4-NO.sub.2   198-200 DCM/iso ether              79 (c)                                                                              ##STR174##                                                                            NH.sub.2    2-OMe                                                                             4-NH.sub.2   229-232 THF/iso ether              80 (l) et (m)                                                                       ##STR175##                                                                            NH.sub.2    2-OMe                                                                              ##STR176##  NMR DCM/iso ether                  81 (l) et (m)                                                                       ##STR177##                                                                             ##STR178## 2-OMe                                                                              ##STR179##  204-210 DCM/iso ether              82 (f)                                                                              ##STR180##                                                                            NH.sub.2    H                                                                                  ##STR181##  170-176 DCM/iso                    __________________________________________________________________________                                               ether                          

(a) Compound prepared according to the procedure described in EXAMPLE 1.

(b) Compound prepared according to the procedure described in EXAMPLE16.

(c) Compound prepared according to the procedure described in EXAMPLE17.

(d) Compound prepared according to the procedure described in step A ofEXAMPLE 27.

(e) Compound prepared according to the procedure described in EXAMPLE 10by using the appropriate amines or the appropriate heterocycles.

(f) Compound prepared according to the procedure described in EXAMPLE30.

(g) Compound prepared according to the procedure described in EXAMPLE11.

(h) Compound prepared according to the procedure described in EXAMPLE13.

(i) Compound prepared according to the procedure described in EXAMPLE 4by using the appropriate acid chlorides.

(j) Compound prepared according to the procedure described in EXAMPLE 5by using the appropriate chloroformates.

(k) Compound prepared according to the procedure described in EXAMPLE 14by using the appropriate acid chlorides.

(l) Compound prepared according to the procedure described in EXAMPLES18 and 19.

(m) Compound prepared according to the procedure described in step B ofEXAMPLE 27 by using the appropriate amines or the appropriateheterocycles.

(n) Compound prepared according to the procedures described in step Aand then step B of EXAMPLE 15.

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 54

2.05 ppm:bs:3H

2.3 ppm:bs:3H

6.5 ppm:s:2H

6.6 to 8.2 ppm:m:11H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 55

1.8 to 2.4 ppm:mt:6H

3.8 ppm:s:3H

6.9 ppm:d:1H

7.2 to 7.8 ppm:mt:4H

7.9 ppm:d:1H

8.1 ppm:mt:3H

8.4 ppm:d:1H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 73

1.9 ppm:s:6H

2.2 ppm:mt:3H

3.1 ppm:t:2H

3.4 ppm:s:3H

3.8 ppm:s:3H

6.6 to 7.8 ppm:10H

8.2 to 8.8 ppm:bs:1H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 80

1.1 ppm:t:6H

2.7 ppm:s:2H

3.2 to 3.5 ppm:qd+s:7H

6.9 ppm:mt:2H

7.1 ppm:t:1H

7.3 to 7.5 ppm:mt:3H

7.6 ppm:s:1H

7.75 to 8.1 ppm:t:of d 3H

8.8 ppm:s:1H

EXAMPLE 835-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-(piperazin-1-yl)indol-2-one

A solution of 0.300 g of the compound obtained in EXAMPLE 65 in 5 ml ofDCM is cooled to 0° C. and 5 ml of TFA are added. The mixture is stirredfor 2 hours at 0° C. and evaporated under vacuum. The residue is takenup with a 5% solution of potassium carbonate, extracted with AcOEt,dried over sodium sulfate and evaporated under vacuum. The residue ischromatographed on silica using a DCM/MeOH mixture (90/10; v/v) as theeluent to give the expected product after crystallization from a DCM/isoether mixture. m=0.105 g. M.p.=210° C.

EXAMPLE 84 3-Amino-5,6-dichloro-1-4-(N',N'-diethylureido)-benzenesulfonyl!-1,3-dihydro-3-phenylindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.293 g of3-amino-5,6-dichloro-1,3-dihydro-3-phenylindol-2-one and 0.290 g of4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography onsilica using a DCM/AcOEt mixture (85/15; v/v) as the eluent gives theexpected product after crystallization from a DCM/iso ether mixture.m=0.26 g. M.p.=119°-121° C.

EXAMPLE 85 3-Amino-4,5-dichloro-1-4-(N',N'-diethylureido)-benzenesulfonyl!-1,3-dihydro-3-phenylindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.4 g of3-amino-4,5-dichloro-1,3-dihydro-3-phenylindol-2-one and 0.4 g of4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography onsilica using a DCM/AcOEt mixture (85/15; v/v) as the eluent gives theexpected product after crystallization from a DCM/iso ether mixture.m=0.46 g. M.p.=161°-163° C.

EXAMPLE 865-Ethoxy-3-(2-ethoxycarbonyl-1-ethoxycarbonylhydrazino)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-phenylindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.500 g of5-ethoxy-3-(2-ethoxycarbonyl-1-ethoxycarbonylhydrazino)-1,3-dihydro-3-phenylindol-2-oneand 0.280 g of 2,4-dimethoxybenzenesulfonyl chloride. The expectedproduct is obtained after crystallization from a DCM/iso ether mixture.m=0.383 g. M.p.=228°-229° C.

EXAMPLE 87 3-Amino-3-(2-chlorophenyl)-5-ethoxy-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 30 from3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and4-(N',N'-diethylureido)benzenesulfonyl chloride.

NMR spectrum at 200 MHz in DMSO-d₆

1.0 ppm:t:6H

1.1 ppm:t:3H

2.95 ppm:s:2H

3.3 ppm:qd:4H

6.2 ppm:d:1H

6.9 ppm:d of d:1H

7.1 ppm:d:1H

7.25 ppm:t:1H

7.4 ppm:t:1H

7.6 to 7.9 ppm:mt:5H

8.1 ppm:d:1H

8.7 ppm:s:1H

EXAMPLE 883-Amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and2,4-dimethoxybenzenesulfonyl chloride. The expected product is obtainedafter crystallization from a DCM/ hexane/iso ether mixture.M.p.=196°-198° C.

EXAMPLE 89 Methyl 4-3-amino-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!methyl-3-methoxybenzoate

A solution of 1.13 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one in 7 ml ofDMF is cooled to 0° C. under an argon atmosphere and 0.120 g of sodiumhydride as an 80% dispersion in oil is added. After stirring for 30minutes, 1 g of methyl 4-bromomethyl-3-methoxybenzoate is added and thereaction mixture is stirred for 1 hour at 0° C. It is poured into waterand the precipitate formed is filtered off, washed with water, taken upwith AcOEt, dried over sodium sulfate and evaporated under vacuum. Theresidue is chromatographed on silica using a DCM/AcOEt mixture (93/7;v/v) as the eluent to give the expected product after crystallizationfrom a DCM/iso ether mixture. m=1.88 g. M.p.=152° C.

EXAMPLE 90 Methyl 4-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-3-(methoxycarboxamido)-2-oxoindol-1-yl!methyl-3-methoxybenzoate

A mixture of 1.67 g of the compound obtained in EXAMPLE 89 and 10 ml ofpyridine is cooled to 0° C. and a solution of 0.669 g of methylchloroformate in 2 ml of DCM is added. The reaction mixture is stirredfor 1 hour at between 0° and +4° C. and poured into water. It isextracted with DCM, washed with a 5% solution of potassiumhydrogensulfate, dried over sodium sulfate and evaporated under vacuum.The residue is chromatographed on silica using a DCM/AcOEt mixture(95/5; v/v) as the eluent to give the expected product aftercrystallization from a DCM/iso ether mixture. m=1.6 g. M.p.=174° C.

EXAMPLE 91 1-4-(N-tert-Butylcarbamoyl)-2-methoxybenzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methoxy-carboxamido)indol-2-oneA) 4-5-Chloro-3-(2-chlorophenyl)-2,3-dihydro-3-(methoxycarboxamido)-2-oxoindol-1-yl!methyl-3-methoxybenzoicacid

0.317 g of lithium hydroxide monohydrate is added to a mixture of 0.8 gof the compound obtained in EXAMPLE 90, 9 ml of THF, 9 ml of MeOH and 3ml of water and the reaction mixture is stirred for 4 hours at RT. Wateris then added and the mixture is acidified to pH 1 by the addition of 1NHCl, extracted with DCM, dried over sodium sulfate and evaporated undervacuum to give the expected product, which is used as such in the nextstep.

B) 1-4-(N-tert-Butylcarbamoyl)-2-methoxybenzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methoxycarboxamido)indol-2-one

A solution of 0.450 g of the compound obtained in the previous step in10 ml of DCM is cooled to 0° C., 0.113 g of DIPEA and 0.403 g of BOP areadded and the mixture is stirred for 15 minutes. 0.095 g oftert-butylamine is then added and the mixture is stirred for 3 hours at0° C. Water is added and the mixture is extracted with DCM, washed witha 5% solution of potassium hydrogensulfate, dried over sodium sulfateand evaporated under vacuum. The residue is chromatographed on silicausing a DCM/AcOEt mixture (90/10; v/v) as the eluent to give theexpected product after crystallization from a DCM/iso ether mixture.m=0.260 g. M.p.=215° C.

EXAMPLE 92 3-Amino-1-4-(N-tert-butylcarbamoyl)-2-methoxybenzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 0.70 g of the compound obtained in EXAMPLE 91 and 35 ml ofa 33% solution of hydrobromic acid in AcOH is stirred for 2 hours at RT.It is evaporated under vacuum at RT and the residue is taken up withwater, rendered alkaline to pH 10 by the addition of sodium carbonate,extracted with AcOEt, dried over sodium sulfate and evaporated undervacuum. The residue is chromatographed on silica using DCM and then aDCM/AcOEt mixture (80/20; v/v) as the eluent to give the expectedproduct after crystallization from a DCM/ iso ether mixture. m=0.370 g.M.p.=234° C.

EXAMPLE 93 tert-Butyl 4-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-3-dimethylamino-2-oxoindol-1-yl!methylbenzoate

This compound is prepared according to the procedure described inEXAMPLE 89 from 1.5 g of5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-dimethylaminoindol-2-one and1.40 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silicausing a gradient of an AcOEt/ hexane mixture (from 10/90; v/v to 20/80;v/v) as the eluent gives the expected product. m=1.5 g.

NMR spectrum at 200 MHz in DMSO-d₆

1.5 ppm:s:9H

2.0 to 2.4 ppm:m:6H

4.8 to 5.2 ppm:d of d:2H

6.8 ppm:d:1H

7.0 ppm:d:1H

7.2 to 7.6 ppm:mt:6H

7.8 ppm:d:2H

8.1 ppm:d:1H

EXAMPLE 94 1-4-(N-tert-Butylcarbamoyl)benzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-dimethylaminoindol-2-oneA) 4-5-Chloro-3-(2-chlorophenyl)-2,3-dihydro-3-dimethylamino-2-oxoindol-1-yl!methylbenzoicacid

A solution of 0.615 g of the compound obtained in EXAMPLE 93 in 2 ml ofDCM is cooled to 0° C. and 2 ml of TFA are added. The mixture is stirredfor 30 minutes and evaporated under vacuum and the residue is then takenup with DCM and evaporated under vacuum again to give the expectedproduct, which is used as such in the next step.

B) 1-4-(N-tert-Butylcarbamoyl)benzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-dimethylaminoindol-2-one

A solution of 0.546 g of the compound obtained in the previous step in 5ml of DCM is cooled to 0° C. and neutralized to pH 7 by the addition ofDIPEA, and 0.530 g of BOP is then introduced. The pH is readjusted to 7by the addition of DIPEA, 0.2 ml of tert-butylamine is added and themixture is stirred for 16 hours, the temperature being allowed to riseto RT. It is evaporated under vacuum, extracted with AcOEt, washed witha 5% solution of sodium carbonate, dried over sodium sulfate andevaporated under vacuum. The residue is chromatographed on silica usinga gradient of a hexane/AcOEt mixture (from 80/20; v/v to 70/30; v/v) asthe eluent to give the expected product after crystallization from aDCM/iso ether mixture. m=0.280 g. M.p.=158° C.

EXAMPLE 95 5-Chloro-3-(2-chlorophenyl)-1-4-(N-1-ethylpropylcarbamoyl)benzyl!-1,3-dihydro-3-dimethylamino-indol-2-one

This compound is prepared according to the procedure described in step Bof EXAMPLE 94 from 0.623 g of the compound obtained in step A of EXAMPLE94 and 0.24 ml of 1-ethylpropylamine, in the presence of 0.605 g of BOPand in the presence of DIPEA in order to maintain a pH of 7.Chromatography on silica using a gradient of a hexane/AcOEt mixture(from 90/10; v/v to 70/30; v/v) as the eluent gives the expected productafter crystallization from a DCM/hexane mixture. m=0.490 g. M.p.=208° C.

EXAMPLE 96 3-Amino-1-4-(N-tert-butylcarbamoyl)benzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneA) tert-Butyl 4-3-amino-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!methylbenzoate

This compound is prepared according to the procedure described inEXAMPLE 89 from 1.0 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1.01 g oftert-butyl 4-bromomethylbenzoate. Chromatography on silica using DCM andthen a DCM/AcOEt mixture (95/5; v/v) as the eluent gives 0.98 g of theexpected product, which is used as such in the next step.

B) 4-3-Amino-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!methylbenzoicacid

A solution of 0.98 g of the compound obtained in the previous step in 2ml of DCM is cooled to 0° C. and 4.5 ml of TFA are added. The mixture isstirred for 30 minutes and evaporated under vacuum and the residue isthen taken up with DCM and evaporated under vacuum again to give theexpected product, which is used as such in the next step.

C) 3-Amino-1-4-(N-tert-butylcarbamoyl)benzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A solution of 0.867 g of the compound obtained in the previous step in 8ml of DCM is cooled to 0° C. and neutralized to pH 7 by the addition ofDIPEA, and 1.12 g of BOP are then introduced. The pH is re-adjusted to 7by the addition of DIPEA, 0.64 ml of tert-butylamine is added and themixture is stirred for 16 hours, the temperature being allowed to riseto RT. It is evaporated under vacuum, extracted with AcOEt, washed witha 5% solution of sodium carbonate, dried over sodium sulfate andevaporated under vacuum. The residue is chromatographed on silica usinga gradient of a hexane/AcOEt mixture (from 80/20; v/v to 70/30; v/v) asthe eluent to give the expected product after crystallization from aDCM/MeOH/iso ether mixture. m=0.610 g. M.p.=173°-178° C.

EXAMPLE 97 3-Acetamido-3-(2-chlorophenyl)-5-ethoxy-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 2 from the compound obtained in EXAMPLE 87 and acetyl chloride.Crystallization from a DCM/iso ether mixture gives the expected product,which crystallizes with 0.25 mol of iso ether.

NMR spectrum at 200 MHz in DMSO-d₆

1.0 ppm:t and d:6H and 12H (iso ether)

1.2 ppm:t:3H

1.8 ppm:s:3H

3.3 ppm:qd:4H

3.55 ppm:sep:2H (iso ether)

3.9 ppm:qd:2H

6.7 ppm:d:1H

6.9 ppm:d of d:1H

7.2 to 7.4 ppm:mt:4H

7.6 to 7.9 ppm:mt:5H

8.7 ppm:s:1H

9.1 ppm:s:1H

EXAMPLE 983-Amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 16 from3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and2-methoxy-4-nitrobenzenesulfonyl chloride. Crystallization from aDCM/iso ether mixture gives the expected product, which crystallizeswith 0.25 mol of iso ether. M.p.=129°-132° C.

EXAMPLE 99 3-Amino-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 30 from3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and4-(N',N'-diethylureido)benzenesulfonyl chloride. M.p.=195°-196° C.

EXAMPLE 100 3-(2-Chlorophenyl)-5-ethoxy-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(methoxycarboxamido)indol-2-one

This compound is prepared according to the procedures described inEXAMPLES 22, then 23 and then 24 from the compound obtained in EXAMPLE98. The expected product is obtained after crystallization fromchloroform. M.p.=263°-266° C.

EXAMPLE 101 3-Amino-3-(2-chlorophenyl)-5-ethoxy-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydroindol-2-onehemihydrate

This compound is prepared according to the procedure described inEXAMPLE 92 from the compound obtained in EXAMPLE 100. M.p.=218°-220° C.

EXAMPLE 1025-Chloro-3-(cyclohexylmethyl)-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)-3-(methylamino)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 16 from 1.49 g of5-chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-(methylamino)indol-2-one and1.8 g of 2-methoxy-4-nitrobenzenesulfonyl chloride. Chromatography onsilica using DCM and then a DCM/AcOEt mixture (95/5; v/v) as the eluentgives 1.5 g of the expected product after crystallization from AcOEt.M.p.=207° C.

EXAMPLE 103 5-Chloro-3-(cyclohexylmethyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(methylamino)indol-2-oneA)5-Chloro-3-(cyclohexylmethyl)-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)-3-(N-methylmethoxycarboxamido)indol-2-one

A solution of 1.62 g of the compound obtained in EXAMPLE 102 in 10 ml ofpyridine is cooled to +4° C., a solution of 0.27 ml of methylchloroformate in 5 ml of DCM is added dropwise and the mixture isstirred for 3 hours at +4° C. 50 ml of water are added to the reactionmixture, extraction is carried out with AcOEt, the organic phase iswashed with a saturated solution of sodium chloride and with water anddried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using DCM as the eluentto give 1.14 g of the expected product after crystallization from aDCM/iso ether mixture.

NMR spectrum at 200 MHz in DMSO-d₆

0.5 to 1.7 ppm:m:11H

1.9 ppm:mt:2H

3.1 ppm:s:3H

3.3 ppm:s:3H

3.7 ppm:s:3H

7.4 to 8.4 ppm:m:6H

B)1-(4-Amino-2-methoxybenzenesulfonyl)-5-chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-(N-methylmethoxycarboxamido)indol-2-one

A mixture of 1.14 g of the compound obtained in the previous step, 0.5 gof Raney® nickel and 50 ml of MeOH is hydrogenated at atmosphericpressure for 20 minutes at RT. The catalyst is filtered off on Celite®and the filtrate is evaporated under vacuum to give 1.19 g of theexpected product after crystallization from MeOH.

NMR spectrum at 200 MHz in DMSO-d₆

0.4 to 1.6 ppm:m:11H

1.8 ppm:mt:2H

3.15 ppm:s:3H

3.35 ppm:s:3H

3.55 ppm:s:3H

6.1 to 7.9 ppm:m:8H

C)5-Chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-(N-methylmethoxycarboxamido)-1-2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl!indol-2-one

A solution of 1.19 g of the compound obtained in the previous step in 10ml of pyridine is cooled to +4° C., a solution of 0.3 ml of phenylchloroformate in 10 ml of DCM is added dropwise and the mixture isstirred for 3 hours at RT. 50 ml of water are added to the reactionmixture, extraction is carried out with AcOEt, the organic phase iswashed with a saturated solution of NaCl and with water and dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is chromatographed on silica using DCM and then a DCM/AcOEtmixture (95/5; v/v) as the eluent to give 0.755 g of the expectedproduct after crystallization from a DCM/iso ether mixture.

D) 5-Chloro-3-(cyclohexylmethyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(N-methylmethoxycarboxamido)indol-2-one

0.09 ml of diethylamine is added to a solution of 0.268 g of thecompound obtained in the previous step in 15 ml of chloroform and thereaction mixture is heated at 60° C. for 3 hours. It is concentratedunder vacuum and the residue is chromatographed on silica using DCM andthen a DCM/AcOEt mixture (85/15; v/v) as the eluent to give 0.18 g ofthe expected product after crystallization from a DCM/iso ether mixture.

NMR spectrum at 200 MHz in DMSO-d₆

0.4 to 2.1 ppm:m:19H

3.15 ppm:s:3H

3.35 ppm:m:7H

3.6 ppm:s:3H

7.2 to 7.9 ppm:m:6H

8.65 ppm:s:1H

E) 5-Chloro-3-(cyclohexylmethyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(methylamino)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 92 from the compound obtained in the previous step. The expectedproduct is obtained after crystallization from a DCM/iso ether mixture.M.p.=210° C.

EXAMPLE 104 5-Chloro-3-(cyclohexylmethyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(N-methylphenoxycarboxamido)indol-2-oneA)1-(4-Amino-2-methoxybenzenesulfonyl)-5-chloro-3-(cyclohexylmethyl)-1,3-dihydro-3-(methylamino)indol-2-one

A mixture of 1.2 g of the compound obtained in EXAMPLE 102, 3 g ofRaney® nickel, 30 ml of MeOH and 40 ml of THF is hydrogenated atatmospheric pressure and at RT. After 40 minutes, the catalyst isfiltered off on Celite® and the filtrate is evaporated under vacuum. Theresidue is chromatographed on silica using DCM and then a DCM/AcOEtmixture (75/25; v/v) as the eluent to give 0.6 g of the expectedproduct, which is used as such in the next step.

B) 5-Chloro-3-(cyclohexylmethyl)-1,3-dihydro-1-2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl!-3-(N-methylphenoxycarboxamido)indol-2-one

A solution of 0.6 g of the compound obtained in the previous step in 2ml of pyridine is cooled to +4° C., a solution of 0.17 ml of phenylchloroformate in 3 ml of DCM is added dropwise and the mixture isstirred for 4 hours, the temperature being allowed to rise to RT. 40 mlof water are added to the reaction mixture, extraction is carried outwith AcOEt, the organic phase is washed with a saturated solution ofsodium chloride and with water and dried over sodium sulfate and thesolvent is evaporated off under vacuum to give 0.9 g of the expectedproduct, which is used as such in the next step.

C) 5-Chloro-3-(cyclohexylmethyl)-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(N-methylphenoxycarboxamido)indol-2-one

0.31 ml of diethylamine is added to a solution of 0.9 g of the compoundobtained in the previous step in 5 ml of chloroform and the mixture isheated at 60° C. for 4 hours. 50 ml of water are added to the reactionmixture, extraction is carried out with AcOEt, the organic phase iswashed with a saturated solution of sodium chloride and with water anddried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using DCM and then aDCM/AcOEt mixture (85/15; v/v) as the eluent to give 0.45 g of theexpected product after crystallization from a DCM/iso ether mixture.M.p.=130° C.

EXAMPLE 1053-Amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(4-methoxy-2-nitrobenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 2 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one and 1.71 g of4-methoxy-2-nitrobenzenesulfonyl chloride. Chromatography on silicausing a DCM/hexane mixture (80/20; v/v) and then DCM as the eluent gives2.8 g of the expected product after crystallization from a DCM/ isoether mixture. M.p.=192°-195° C.

EXAMPLE 1063-Amino-1-(2-amino-4-methoxybenzenesulfonyl)-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

A mixture of 2.4 g of the compound obtained in EXAMPLE 105, 1 g ofRaney® nickel, 50 ml of MeOH and 50 ml of THF is hydrogenated atatmospheric pressure for 1 hour at RT. The catalyst is filtered off onCelite® and the filtrate is evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5;v/v) as the eluent to give 0.316 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=160°-166° C.

EXAMPLE 107 3-Amino-5-chloro-3-(2-chlorophenyl)-1-2-(ethylamino)-4-methoxybenzenesulfonyl!-1,3-dihydro-indol-2-one

2.6 ml of AcOH and then 0.09 ml of acetaldehyde and 0.038 g of sodiumcyanoborohydride are added at RT to a solution of 0.830 g of thecompound obtained in EXAMPLE 106 in 22 ml of MeOH. After stirring for 4hours at RT, 2 drops of concentrated HCl are added and the reactionmixture is then neutralized by the addition of a 5% solution ofpotassium carbonate. The solvent is concentrated under vacuum, theresidue is extracted with AcOEt, the organic phase is washed with waterand with a saturated solution of sodium chloride and dried over sodiumsulfate and the solvent is evaporated off under vacuum. The residue ischromatographed on silica using a DCM/hexane mixture (80/20; v/v) andthen DCM as the eluent to give 0.396 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=192°-196° C.

EXAMPLE 108 3-Amino-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one, (+)isomer

This compound is prepared according to the procedure described inEXAMPLE 30 from 0.293 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one, (+) isomer,and 0.290 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride.Chromatography on silica using a DCM/AcOEt mixture (90/10; v/v) as theeluent gives 0.24 g of the expected product after crystallization from aDCM/iso ether mixture. α_(D) ²⁵ =+127° (c=0.24; chloroform).

EXAMPLE 109 3-Amino-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one, (-)isomer

This compound is prepared according to the procedure described inEXAMPLE 30 from 0.293 g of3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one, (-) isomer,and 0.290 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride.Chromatography twice on silica using a DCM/AcOEt mixture (90/10; v/v) asthe eluent gives 0.065 g of the expected product after crystallizationand then recrystallization from a DCM/iso ether mixture and drying at90° C. under vacuum. α_(D) ²⁵ =-133° (c=0.24; chloroform).

EXAMPLE 110 5-Chloro-1-4-(2-chlorobenzamido)benzenesulfonyl!-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)-indol-2-oneA)5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)-1-(4-nitrobenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 11 from 7.03 g of5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)-indol-2-one and5.73 g of 4-nitrobenzenesulfonyl chloride. Chromatography on silicausing DCM as the eluent gives 7.76 g of the expected product aftercrystallization from iso ether. M.p.=220°-221° C.

B)1-(4-Aminobenzenesulfonyl)-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)indol-2-one

A mixture of 7.7 g of the compound obtained in the previous step, 3 g ofRaney® nickel, 140 ml of EtOH and 150 ml of THF is hydrogenated atatmospheric pressure and at RT. The catalyst is filtered off on Celite®and the filtrate is concentrated under vacuum to give 6.3 g of theexpected product after crystallization from iso ether. M.p.=240° C.

C) 5-Chloro-1-4-(2-chlorobenzamido)benzenesulfonyl!-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)indol-2-one

A solution of 0.7 g of the compound obtained in the previous step in 100ml of DCM is cooled to +5° C., 2.5 ml of triethylamine are added, asolution of 0.35 ml of 2-chlorobenzoyl chloride in 4 ml of DCM is thenadded dropwise and the reaction mixture is stirred for 12 hours, thetemperature being allowed to rise to RT. It is concentrated undervacuum, the residue is extracted with AcOEt, the organic phase is washedwith water and dried over sodium sulfate and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica using DCM asthe eluent to give 0.31 g of the expected product after crystallizationfrom iso ether. M.p.=221°-222° C.

EXAMPLE 111 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)-1-4-(nicotinoylamino)benzenesulfonyl!-indol-2-one

A solution of 0.5 g of the compound obtained in step B of EXAMPLE 110 in5 ml of DCM is cooled to +5° C., 1.5 ml of triethylamine and then 0.1 gof 4-dimethylaminopyridine are added and a solution of 0.64 g ofnicotinoyl chloride hydrochloride in 15 ml of DCM is added dropwise. Thereaction mixture is stirred for 19 hours, the temperature being allowedto rise to RT, and concentrated under vacuum. The residue is taken upwith water and extracted with AcOEt, the organic phase is washed withwater and dried over sodium sulfate and the solvent is evaporated offunder vacuum to give 0.41 g of the expected product, which contains 0.25mol of iso ether after crystallization from iso ether. M.p.=228° C.

EXAMPLE 112 5-Chloro-3-(2-chlorophenyl)-1- 4-N-(1-ethoxycarbonyl-1-methylethyl)carbamoyl!-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(methylamino)indol-2-oneA) Benzyl 4-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-3-(methylamino)-2-oxoindol-1-yl!sulfonyl!-3-methoxybenzoate

This compound is prepared according to the procedure described in step Aof EXAMPLE 28 from 6 g of5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(methylamino)-indol-2-one and6.66 g of benzyl 4-chlorosulfonyl-3-methoxybenzoate. 10.3 g of theexpected product are obtained after crystallization from iso ether.

NMR spectrum at 200 MHz in DMSO-d₆

1.95 ppm:d:3H

3.55 ppm:qd:1H

3.7 ppm:s:3H

5.3 ppm:s:2H

6.6 to 8.2 ppm:m:15H

B) 4-5-Chloro-3-(2-chlorophenyl)-2,3-dihydro-3-(methylamino)-2-oxoindol-1-yl!sulfonyl!-3-methoxybenzoicacid

A mixture of 10.3 g of the compound obtained in the previous step, 1 gof 10% palladium-on-charcoal and 300 ml of AcOEt is hydrogenolyzed atatmospheric pressure and at RT. The catalyst is filtered off on Celite®and the filtrate is concentrated under vacuum to give 8.05 g of theexpected product after crystallization from iso ether. M.p.=248° C.

C) 5-Chloro-3-(2-chlorophenyl)-1- 4-N-(1-ethoxycarbonyl-1-methylethyl)carbamoyl!-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(methylamino)indol-2-one

1.02 g of DIPEA, 3.5 g of BOP and 1.91 g of ethyl2-amino-2-methylpropionate hydrochloride are added successively at RT toa solution of 2 g of the compound obtained in the previous step in 25 mlof DCM. After stirring for 2 hours 30 minutes at RT, the reactionmixture is concentrated under vacuum, the residue is taken up with waterand extracted with AcOEt, the organic phase is dried over sodium sulfateand the solvent is evaporated off under vacuum. The residue ischromatographed on silica using DCM and then a DCM/ AcOEt mixture (95/5;v/v) as the eluent to give 0.708 g of the expected product aftercrystallization from iso ether. M.p.=141° C.

EXAMPLE 113 5-Chloro-3-(2-chlorophenyl)-1- 4-(2-furoyl)-amino!-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(dimethylamino)indol-2-one

A solution of 0.45 g of the compound obtained in EXAMPLE 56 in 5 ml ofDCM is cooled to 0° C. and 0.6 ml of triethylamine and then 0.1 ml of2-furoyl chloride and 0.02 g of 4-dimethylaminopyridine are added. Themixture is stirred for 1 hour at RT, 0.1 ml of 2-furoyl chloride isadded and the reaction mixture is stirred for 12 hours at RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with AcOEt, the organic phase is washed with a 5% solution ofsodium carbonate, with water and with a saturated solution of sodiumchloride and dried over sodium sulfate and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica using DCM andthen a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.511 g ofthe expected product after crystallization from a DCM/iso ether mixture.M.p.=255° C.

EXAMPLE 114 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-(2-hydroxyethyl)amino!indol-2-one

A solution of 1.084 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(trimethylsilyloxy)ethyl!-amino!indol-2-one in 20 ml of DMF is cooledto 0° C. under an argon atmosphere and 0.111 g of sodium hydride as a60% dispersion in oil is added. After stirring for 25 minutes, 0.78 g of4-(N',N'-diethylureido)-benzenesulfonyl chloride is added and thereaction mixture is stirred for 3 hours at RT. It is poured into waterand extracted with AcOEt, the organic phase is washed with water andwith a saturated solution of NaCl and dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using a DCM/AcOEt mixture (70/30; v/v) as the eluent to give0.505 g of the expected product after crystallization and thenrecrystallization from a DCM/iso ether mixture. M.p.=192°-193° C.

EXAMPLE 115 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-2-(2-hydroxyethoxy)ethyl!amino!indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 114 from 1.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3- 2-2-(trimethylsilyloxy)ethoxy!ethyl!amino!indol-2-one and 1.03 g of4-(N',N'-diethylureido)benzenesulfonyl chloride. Chromatography onsilica using a DCM/AcOEt mixture (50/50; v/v) as the eluent gives 1 g ofthe expected product after crystallization from a DCM/iso ether mixture.M.p.=114°-118° C.

EXAMPLE 116 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-4-(1,1-dimethylpropyl)benzenesulfonyl!-3-2-(morpholin-4-yl)ethyl!amino!indol-2-one

A solution of 1 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-2-(morpholin-4-yl)ethyl!amino!-indol-2-one in 10 ml of DMF is cooled to0° C. under an argon atmosphere and 0.108 g of sodium hydride as a 60%dispersion in oil is added. After stirring for 30 minutes, 0.607 g of4-(1,1-dimethylpropyl)benzenesulfonyl chloride is added and the reactionmixture is stirred for 2 hours, the temperature being allowed to rise toRT. It is poured into water and extracted with AcOEt, the organic phaseis washed with water and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing a DCM/AcOEt mixture (80/20; v/v) as the eluent to give 0.45 g ofthe expected product after crystallization from a DCM/iso ether mixture.M.p.=147° C.

EXAMPLE 117 3-(1S)-5-(Benzyloxycarbonylamino)-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 30 from 1.44 g of the compound obtained in Preparation 54(isomer A) and 0.738 g of 4-(N',N'-diethylureido)benzenesulfonylchloride. Chromatography on silica using a DCM/AcOEt mixture (85/15;v/v) as the eluent gives 1.10 g of the expected product in the form of athick oil. α_(D) ²⁵ =+65.5° (c=0.281; chloroform).

EXAMPLE 118 3-(1S)-5-(Benzyloxycarbonylamino)-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 30 from 0.8 g of the compound obtained in Preparation 55 (isomerB) and 0.410 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride.Chromatography on silica using a DCM/AcOEt mixture (80/20; v/v) as theeluent gives 0.85 g of the expected product in the form of an oil. α_(D)²⁵ =-66.9° (c=0.245; chloroform).

EXAMPLE 119 3-(1R)-5-(Benzyloxycarbonylamino)-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 30 from 0.899 g of the compound obtained in Preparation 56(isomer A) and 0.445 g of 4-(N',N'-diethylureido)benzenesulfonylchloride. Chromatography on silica using a gradient of a DCM/AcOEtmixture (from 95/5; v/v to 85/15; v/v) as the eluent gives 0.68 g of theexpected product in the form of a foam. α_(D) ²⁵ =-60.5° (c=0.249;chloroform).

EXAMPLE 120 3-(1R)-5-(Benzyloxycarbonylamino)-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 30 from 0.88 g of the compound obtained in Preparation 57(isomer B) and 0.449 g of 4-(N',N'-diethylureido)benzenesulfonylchloride. Chromatography on silica using a DCM/AcOEt mixture (80/20;v/v) as the eluent gives 0.65 g of the expected product in the form of afoam. α_(D) ²⁵ =+92.50° (c=0.245; chloroform).

EXAMPLE 121 3-(1S)-5-Amino-1-(methoxycarbonyl)pentyl!-amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-onetrifluoroacetate A) 3-(1S)-5-Amino-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-benzenesulfonyl!-1,3-dihydroindol-2-one

A solution of 1.0 g of the compound obtained in EXAMPLE 117 in 5 ml ofDCM is cooled to 0° C. and 15 ml of TFA and then 0.8 g of anisole and 3ml of trifluoromethanesulfonic acid are added. The mixture is stirredfor 22 minutes at 0° C. ether is then added to the reaction mixture andthe precipitate formed is filtered off. The precipitate is dissolved inAcOEt, the organic phase is washed with a 5% solution of potassiumcarbonate and with water and dried over sodium sulfate and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing a DCM/MeOH/ triethylamine mixture (90/10/1; v/v/v) as the eluent.The product obtained is dissolved in AcOEt, the organic phase is washedtwice with a 5% solution of potassium carbonate and with a saturatedsolution of NaCl and dried over sodium sulfate and the solvent isevaporated off under vacuum to give 0.7 g of the expected product, whichis used as such.

B) 3-(1S)-5-(tert-Butoxycarbonylamino)-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

A mixture of 0.684 g of the compound obtained in the previous step, 0.26g of di-tert-butyl dicarbonate, 0.1 g of triethylamine and 5 ml of THFis stirred for 3 hours at RT. The reaction mixture is concentrated undervacuum and the residue is chromatographed on silica using a DCM/AcOEtmixture (80/20; v/v) as the eluent to give 0.46 g of the expectedproduct, which is used as such.

C) 3-(1S)-5-Amino-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-benzenesulfonyl!-1,3-dihydroindol-2-onetrifluoroacetate

A solution of 0.46 g of the compound obtained in the previous step in 3ml of DCM is cooled to 0° C., 4 ml of TFA are added and the reactionmixture is stirred for 3 hours at 0° C. It is concentrated under vacuum,the residue is extracted with AcOEt, the organic phase is washed threetimes with water and with a saturated solution of NaCl and dried oversodium sulfate and the solvent is evaporated off under vacuum. Theresidue is taken up with iso ether and, after trituration, the solidformed is filtered off to give 0.35 g of the expected product in theform of a solid containing 0.33 mol of iso ether. M.p.=140° C. α_(D) ²⁵=+69.8° (c =0.3; MeOH).

EXAMPLE 1225-Chloro-3-(2-chlorophenyl)-3-(ethoxycarboxamido)-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 22 from 4.75 g of the compound obtained in EXAMPLE 16 and 1.81ml of ethyl chloroformate. Chromatography on silica using a DCM/ hexanemixture (90/10; v/v) and then DCM as the eluent gives 4.7 g of theexpected product after crystallization from a DCM/iso ether mixture.M.p.=155°-160° C.

EXAMPLE 1235-Chloro-3-(2-chlorophenyl)-3-(ethoxycarboxamido)-1,3-dihydro-1-2-methoxy-4- (morpholin-4-yl)-carbonylamino!benzenesulfonyl!indol-2-oneA)1-(4-Amino-2-methoxybenzenesulfonyl)-5-chloro-3-(2-chlorophenyl)-3-(ethoxycarboxamido)-1,3-dehydroindol-2-one

A mixture of 4.45 g of the compound obtained in EXAMPLE 122, 1 g ofRaney® nickel, 30 ml of MeOH and 60 ml of THF is hydrogenated atatmospheric pressure for 1 hour at RT. The catalyst is filtered off onCelite® and the filtrate is evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5;v/v) as the eluent to give 3.62 g of the expected product, which is usedas such.

B) 5-Chloro-3-(2-chlorophenyl)-3-(ethoxycarboxamido)-1,3-dihydro-1-2-methoxy-4-(phenoxycarboxamido)-benzenesulfonyl!indol-2-one

A solution of 3.6 g of the compound obtained in the previous step in 7ml of pyridine is cooled to 0°-5° C. and a solution of 0.9 ml of phenylchloroformate in 10 ml of DCM is added. The mixture is stirred for 1hour at RT, water is then added to the reaction mixture, extraction iscarried out with AcOEt, the organic phase is washed with water and witha saturated solution of NaCl and dried over sodium sulfate and thesolvent is evaporated off under vacuum. The residue is chromatographedon silica using DCM and then a DCM/ AcOEt mixture (95/5; v/v) as theeluent to give 3.55 g of the expected product, which is used as such.

C) 5-Chloro-3-(2-chlorophenyl)-3-(ethoxycarboxamido)-1,3-dihydro-1-2-methoxy-4- (morpholin-4-yl)carbonylamino!benzenesulfonyl!indol-2-one

A mixture of 0.6 g of the compound obtained in the previous step, 0.16ml of morpholine and 10 ml of THF is heated at 60° C. for 4 hours. Aftercooling, the precipitate formed is filtered off and dried to give 0.552g of the expected product containing 0.33 mol of THF. M.p.=255°-260° C.

EXAMPLE 124 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-N'-methyl-N'-(2-dimethylaminoethyl)ureido!indol-2-one A)5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-(phenoxycarboxamido)indol-2-one

0.275 g of phenyl chloroformate is added to a solution of 0.8 g of thecompound obtained in EXAMPLE 99 in 10 ml of pyridine and the mixture isstirred for 18 hours at RT. It is concentrated under vacuum, the residueis extracted with AcOEt, the organic phase is washed with water and witha 5% solution of potassium hydrogensulfate and dried over sodium sulfateand the solvent is evaporated off under vacuum. The residue ischromatographed on silica using a DCM/AcOEt mixture (90/10; v/v) as theeluent to give 0.63 g of the expected product, which is used as such.

B) 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-N'-methyl-N'-(2-dimethylaminoethyl)ureido!indol-2-one

A mixture of 0.63 g of the compound obtained in the previous step, 0.15g of N,N,N'-trimethylethylenediamine, 10 ml of chloroform and 10 ml ofEtOH is heated at 60° C. for 18 hours. It is concentrated under vacuumand the residue is chromatographed on silica using a DCM/MeOH mixture(90/10; v/v) as the eluent to give 0.35 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=155° C.

EXAMPLE 125 3-N'-(Carbamoylmethyl)-N'-methylureido!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-benzenesulfonyl!-1,3-dihydroindol-2-onehemihydrate

A mixture of 1 g of the compound obtained in step A of EXAMPLE 124,0.224 g of sarcosinamide hydrochloride, 0.234 g of DIPEA and 20 ml ofchloroform is heated at 60° C. for 3 hours. It is concentrated undervacuum and the residue is chromatographed on silica using a DCM/MeOHmixture (97/3; v/v) as the eluent to give 0.65 g of the expected productafter crystallization from a DCM/iso ether mixture. M.p.=150° C.

EXAMPLE 126 3-(1R)-5-Amino-1-(methoxycarbonyl)pentyl!-amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-onetrifluoroacetate A) 3-(1R)-5-Amino-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-benzenesulfonyl!-1,3-dihydroindol-2-one

A solution of 0.37 g of the compound obtained in EXAMPLE 120 in 7.5 mlof TFA is cooled to 0° C. and 0.2 g of anisole and 0.8 ml oftrifluoromethanesulfonic acid are then added. The mixture is stirred for22 minutes at 0° C., 50 ml of ether are then added to the reactionmixture and the precipitate formed is filtered off. The precipitate isdissolved in AcOEt, the organic phase is washed with a 5% solution ofpotassium carbonate to pH 9 and with water and dried over sodium sulfateand the solvent is evaporated off under vacuum to give 0.27 g of theexpected product, which is used as such.

B) 3-(1R)-5-(tert-Butoxycarbonylamino-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

A mixture of 0.254 g of the compound obtained in the previous step,0.098 g of di-tert-butyl dicarbonate, 0.05 ml of triethylamine and 4 mlof THF is stirred for one week at RT. The reaction mixture isconcentrated under vacuum and the residue is chromatographed on silicausing a gradient of a DCM/AcOEt mixture (from 90/10; v/v to 80/20; v/v)as the eluent to give 0.17 g of the expected product, which is used assuch.

C) 3-(1R)-5-Amino-1-(methoxycarbonyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)-benzenesulfonyl!-1,3-dihydroindol-2-onetrifluoroacetate

A solution of 0.17 g of the compound obtained in the previous step in0.5 ml of DCM is cooled to 0° C., 2 ml of TFA are added and the reactionmixture is stirred for 2 hours at 0° C. It is concentrated under vacuum,the residue is taken up with DCM and the solvent is evaporated off undervacuum. The residue is taken up with a DCM/iso ether mixture and, aftertrituration, the solid formed is filtered off to give 0.07 g of theexpected product in the form of a foam after drying at 60° C. α_(D) ²⁵=+82.2° (c=0.16; chloroform).

NMR spectrum at 200 MHz in DMSO-d₆

0.9 to 1.18 ppm:m:12H

2.75 ppm:t:2H

3.0 ppm:qd:1H

3.35 ppm:qd:4H

3.6 ppm:s:3H

3.9 ppm:d:1H

6.7 to 8.3 ppm:m:14H

8.8 ppm:s:1H

The compounds according to the invention collected in TABLE III beloware prepared from the 1,3-dihydroindol-2-ones described in thePreparations by following the procedures described in the EXAMPLESabove.

                                      TABLE III                                   __________________________________________________________________________     ##STR182##                                                                                                                        Salt, solvate;                                                                M.p. °C. or                                                            NMR;                                                                          cristallization          Example                                                                             R.sub.3    R.sub.4          R.sub.5                                                                            R.sub.6       solvent                  __________________________________________________________________________    127 (a)                                                                              ##STR183##                                                                              NHMe             H                                                                                   ##STR184##   255-228 DCM/iso                                                               ether                    128 (a)                                                                              ##STR185##                                                                              NHMe             H                                                                                   ##STR186##   169 DCM/iso ether        129 (a)                                                                              ##STR187##                                                                              NHCH.sub.2 CH.sub.2 CN                                                                         H                                                                                   ##STR188##   180 DCM/iso ether        130 (a)                                                                              ##STR189##                                                                              NHMe             H                                                                                   ##STR190##   0.5 DCM 96 DCM/iso                                                            ether                    131 (b)                                                                              ##STR191##                                                                              NHMe             H                                                                                   ##STR192##   223 iso ether            132 (b)                                                                              ##STR193##                                                                              NHMe             H                                                                                   ##STR194##   0.25 DCM 153-154 iso                                                          ether                    133 (b)                                                                              ##STR195##                                                                              NHMe             H                                                                                   ##STR196##   251 DCM                  134 (b)                                                                              ##STR197##                                                                              NHMe             H                                                                                   ##STR198##   239 DCM                  135 (c)                                                                              ##STR199##                                                                              NHMe             2-OMe                                                                               ##STR200##   0.25 H.sub.2 O 162                                                            iso ether                136 (c)                                                                              ##STR201##                                                                              NHMe             2-OMe                                                                               ##STR202##   150 iso ether            137 (c)                                                                              ##STR203##                                                                              NHMe             2-OMe                                                                               ##STR204##   220 DCM/iso ether        138 (a)                                                                              ##STR205##                                                                               ##STR206##      H                                                                                   ##STR207##   224 DCM/iso ether        139 (a)                                                                              ##STR208##                                                                               ##STR209##      H                                                                                   ##STR210##   212 DCM/iso ether        140 (a)                                                                              ##STR211##                                                                               ##STR212##      H                                                                                   ##STR213##   207 DCM/iso ether        141 (a)                                                                              ##STR214##                                                                               ##STR215##      H                                                                                   ##STR216##   232 DCM/iso ether        142 (a) 142990                                                                       ##STR217##                                                                               ##STR218##      H                                                                                   ##STR219##   158-160 DCM/iso                                                               ether                    143 (a)                                                                              ##STR220##                                                                               ##STR221##      H                                                                                   ##STR222##   138-142 DCM/iso                                                               ether                    144 (a)                                                                              ##STR223##                                                                               ##STR224##      H                                                                                   ##STR225##   120 DCM/iso ether        145 (d)                                                                              ##STR226##                                                                               ##STR227##      2-OMe                                                                              4-NO.sub.2    75-76                    146 (e), (f) et (g)                                                                  ##STR228##                                                                               ##STR229##      2-OMe                                                                               ##STR230##   190-195 DCM/iso                                                               ether                    147 (a)                                                                              ##STR231##                                                                               ##STR232##      H                                                                                   ##STR233##   95-100 DCM/iso                                                                ether/hexane             148 (a)                                                                              ##STR234##                                                                               ##STR235##      H                                                                                   ##STR236##   135-138 DCM/iso                                                               ether                    149 (a)                                                                              ##STR237##                                                                               ##STR238##      H                                                                                   ##STR239##   208 DCM/iso ether        150 (a)                                                                              ##STR240##                                                                               ##STR241##      H                                                                                   ##STR242##   155-158 DCM/iso                                                               ether                    151 (h)                                                                              ##STR243##                                                                              NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 NHBoc                                                     2-OMe                                                                              4-OMe         111 DCM/iso ether        152 (h)                                                                              ##STR244##                                                                              NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 NHBoc                                                     3-OMe                                                                              4-OMe         oil NMR                  153 (a)                                                                              ##STR245##                                                                              NH(CH.sub.2).sub.2 O(CH.sub.2).sub.2 NHBoc                                                     H                                                                                   ##STR246##   165 DCM/iso ether        154 (h)                                                                              ##STR247##                                                                              NH(CH.sub.2).sub.3 OMe                                                                         3-OMe                                                                              4-OMe         158-160 DCM/iso                                                               ether                    155 (a)                                                                              ##STR248##                                                                              NH(CH.sub.2).sub.3 OMe                                                                         H                                                                                   ##STR249##   175 DCM/iso ether        156 (a)                                                                              ##STR250##                                                                               ##STR251##      H                                                                                   ##STR252##   oxalate; 155                                                                  isopropanol              157 (h)                                                                              ##STR253##                                                                               ##STR254##      3-OMe                                                                              4-OMe         127 DCM/iso ether        158 (a)                                                                              ##STR255##                                                                               ##STR256##      H                                                                                   ##STR257##   123 pentane              159 (a)                                                                              ##STR258##                                                                               ##STR259##      H                                                                                   ##STR260##   180 DCM/iso ether        160 (a)                                                                              ##STR261##                                                                               ##STR262##      H                                                                                   ##STR263##   oxalate 138 ether        161 (a)                                                                              ##STR264##                                                                               ##STR265##      H                                                                                   ##STR266##   NMR                      162 (a)                                                                              ##STR267##                                                                               ##STR268##      H                                                                                   ##STR269##   159 DCM/iso ether        163 (a)                                                                              ##STR270##                                                                              NH(CH.sub.2).sub.4 NHBoc                                                                       H                                                                                   ##STR271##   178-179 DCM/iso                                                               ether                    164 (h)                                                                              ##STR272##                                                                              NH(CH.sub.2).sub.5 NHBoc                                                                       3-OMe                                                                              4-OMe         0.5 H.sub.2 O                                                                 155-156 DCM/iso                                                               ether                    165 (a)                                                                              ##STR273##                                                                              NH(CH.sub.2).sub.5 NHBoc                                                                       H                                                                                   ##STR274##   175-177 DCM/iso                                                               ether                    166 (a)                                                                              ##STR275##                                                                               ##STR276##      H                                                                                   ##STR277##   206 DCM/iso ether        167 (i)                                                                              ##STR278##                                                                               ##STR279##      H    4-NO.sub.2    140 iso ether/                                                                hexane                   168 (j)                                                                              ##STR280##                                                                               ##STR281##      H    4-NH.sub.2    173 DCM/iso ether        169 (k)                                                                              ##STR282##                                                                               ##STR283##      H                                                                                   ##STR284##   204 DCM/iso ether        170 (a)                                                                              ##STR285##                                                                               ##STR286##      H                                                                                   ##STR287##   174-176 DCM/iso                                                               ether                    171 (a)                                                                              ##STR288##                                                                               ##STR289##      H                                                                                   ##STR290##   133-138 DCM/hexane/                                                           iso ether                172 (a)                                                                              ##STR291##                                                                               ##STR292##      H                                                                                   ##STR293##   180 DCM/iso ether        173 (h)                                                                              ##STR294##                                                                               ##STR295##      3-OMe                                                                              4-OMe         0.33 iso ether;                                                               85-88 DCM/iso ether      174 (a)                                                                              ##STR296##                                                                               ##STR297##      H                                                                                   ##STR298##   184-187 DCM/iso                                                               ether                    175 (a)                                                                              ##STR299##                                                                               ##STR300##      H                                                                                   ##STR301##   0.5 H.sub.2 O 168                                                             DCM/iso ether            176 (a)                                                                              ##STR302##                                                                               ##STR303##      H                                                                                   ##STR304##   0,5 H.sub.2 O 154                                                             DCM/iso ether            177 (a)                                                                              ##STR305##                                                                               ##STR306##      H                                                                                   ##STR307##   130 DCM/iso ether        178 (a)                                                                              ##STR308##                                                                               ##STR309##      H                                                                                   ##STR310##   164 DCM/iso ether        179 (a)                                                                              ##STR311##                                                                              NH(CH.sub.2).sub.3 COOMe                                                                       H                                                                                   ##STR312##   151 DCM/iso ether        180 (a)                                                                              ##STR313##                                                                              NH(CH.sub.2).sub.3 COOBz                                                                       H                                                                                   ##STR314##   149 DCM/iso ether        181 (a)                                                                              ##STR315##                                                                              NHCH.sub.2 CN    H                                                                                   ##STR316##   201 DCM/iso ether        182 (a)                                                                              ##STR317##                                                                              NH(CH.sub.2).sub.5 CN                                                                          H                                                                                   ##STR318##   176-180 DCM/iso                                                               ether                    183 (a)                                                                              ##STR319##                                                                               ##STR320##      H                                                                                   ##STR321##   220 DCM/iso ether        184 (a)                                                                              ##STR322##                                                                               ##STR323##      H                                                                                   ##STR324##   203-205 DCM/iso                                                               ether                    185 (a)                                                                              ##STR325##                                                                               ##STR326##      H                                                                                   ##STR327##   132-135 DCM/iso                                                               ether                    186 (a)                                                                              ##STR328##                                                                               ##STR329##      H                                                                                   ##STR330##   137 DCM/iso ether        187 (a)                                                                              ##STR331##                                                                               ##STR332##      H                                                                                   ##STR333##   174 DCM/iso ether        188 (l)                                                                              ##STR334##                                                                              NHCOOEt          2-OMe                                                                               ##STR335##   254-257 THF              189 (m)                                                                              ##STR336##                                                                               ##STR337##      H                                                                                   ##STR338##   195-RMN DCM/iso                                                               ether                    190 (m)                                                                              ##STR339##                                                                               ##STR340##      H                                                                                   ##STR341##   173 DCM/iso ether        191 (n)                                                                              ##STR342##                                                                              NH.sub.2         2-OMe                                                                              4-CONHtBu     269 DCM/iso              __________________________________________________________________________                                                         ether                

(a) Compound prepared according to the procedure described in EXAMPLE30.

(b) Compound prepared according to the procedure described in step C ofEXAMPLE 110 from the compound obtained in step B of EXAMPLE 110 by usingthe appropriate acid chlorides.

(c) Compound prepared according to the procedure described in step C ofEXAMPLE 112 from the compound obtained in step B of EXAMPLE 112 by usingthe appropriate amines.

(d) Compound prepared according to the procedure described in EXAMPLE16.

(e) Compound prepared according to the procedure described in EXAMPLE103, step B.

(f) Compound prepared according to the procedure described in step A ofEXAMPLE 27.

(g) Compound prepared according to the procedure described in step B ofEXAMPLE 27.

(h) Compound prepared according to the procedure described in EXAMPLE 1.

(i) Compound prepared according to the procedure described in EXAMPLE11.

(j) Compound prepared according to the procedure described in EXAMPLE110, step B.

(k) Compound prepared according to the procedures described in step Aand then step B of EXAMPLE 15.

(l) Compound prepared according to the procedure described in step C ofEXAMPLE 123 using 1-methylpiperazine.

(m) Compound prepared according to the procedure described in step B ofEXAMPLE 124 using the appropriate amines or heterocycles.

(n) Compound prepared according to the procedures described in steps A,C and then D of EXAMPLE 28.

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 152

1.35 ppm:s:9H

2.4 ppm:mt:2H

3.1 ppm:qd:2H

3.3 to 3.7 ppm:m:5H

3.75 to 3.95 ppm:2s:6H

6.65 to 8.20 ppm:m:11H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 161

1.1 ppm:t:6H

1.3 to 2.9 ppm:m:15H

3.3 ppm:qd:4H

6.6 to 8.1 ppm:m:11H

8.75 ppm:s:1H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 189

1.0 ppm:t:6H

1.4 to 1.8 ppm:m:8H

1.8 to 2.3 ppm:mt:2H

2.5 ppm:s:3H

2.8 to 3.7 ppm:m:6H

7.1 to 7.9 ppm:m:11H

8.65 ppm s:1H

9.1 ppm bs:1H

EXAMPLE 192 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-(piperid-4-yl)-amino!indol-2-one hydrobromide

A mixture of 1 g of the compound obtained in EXAMPLE 140 and 40 ml of a33% solution of hydrobromic acid in AcOH is stirred for 18 hours at RT.The reaction mixture is concentrated under vacuum at 30° C., the residueis taken up with ether and the precipitate formed is filtered off togive 0.425 g of the expected product after crystallization from anMeOH/iso ether mixture. M.p.=210° C.

EXAMPLE 193 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-(piperid-4-yl)-methyl!amino!indol-2-one trifluoroacetate

A solution of 0.5 g of the compound obtained in EXAMPLE 141 in 6 ml ofDCM is cooled to 0° C., 6 ml of TFA are added and the reaction mixtureis stirred for two hours at 0° C. It is concentrated under vacuum andthe residue is taken up with DCM and evaporated under vacuum. Theresidue is taken up with ether and the precipitate formed is filteredoff to give 0.34 g of the expected product after crystallization from anMeOH/iso ether mixture. M.p.=218° C.

EXAMPLE 194 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-2-(piperid-4-yl)ethyl!amino!indol-2-one

A solution of 0.63 g of the compound obtained in EXAMPLE 142 in 4 ml ofDCM is cooled to 0° C., 7 ml of TFA are added and the reaction mixtureis stirred for 5 hours 30 minutes at 0° C. It is concentrated undervacuum, the residue is taken up with a 5% solution of sodium carbonateand extracted with AcOEt, the organic phase is washed with water anddried over magnesium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a DCM/MeOH/triethylamine mixture (85/15/2; v/v/v) as the eluent. The productobtained is chromatographed again on silica using aDCM/MeOH/triethylamine mixture (90/10/0.5; v/v/v) as the eluent. Theproduct obtained is dissolved in AcOEt, the organic phase is washed withwater and with a saturated solution of sodium chloride and dried overmagnesium sulfate and the solvent is evaporated off under vacuum to give0.085 g of the expected product after trituration in hexane and thenfiltration.

NMR spectrum at 200 MHz in DMSO-d₆

0.6 to 1.5 ppm:m:13H

1.8 to 2.95 ppm:m:6H

3.3 ppm:qd:4H

6.6 to 8.1 ppm:m:11H

8.7 ppm:s:1H

EXAMPLE 195 3-2-(2-Aminoethoxy)ethyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)indol-2-one1.25 trifluoroacetate

A solution of 0.618 g of the compound obtained in EXAMPLE 151 in 2.6 mlof DCM is cooled to 0° C. and 7.7 ml of TFA are added. The mixture isstirred for 2 hours at 0° C. and concentrated under vacuum to give 0.506g of the expected product after crystallization from a DCM/iso ethermixture. M.p.=145°-148° C.

EXAMPLE 196 3-2-(2-Aminoethoxy)ethyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-(3,4-dimethoxybenzenesulfonyl)indol-2-onetrifluoroacetate

This compound is prepared according to the procedure described inEXAMPLE 195 from 2 g of the compound obtained in EXAMPLE 152 in 8.3 mlof DCM and 24.9 ml of TFA. 1.44 g of the expected product are obtainedafter crystallization from a DCM/THF/iso ether mixture. M.p.=110°-114°C.

EXAMPLE 197 3-2-(2-Aminoethoxy)ethyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-4-(N',N'-diethylureido)benzenesulfonyl!indol-2-one trifluoroacetate

This compound is prepared according to the procedure described inEXAMPLE 195 from 2.3 g of the compound obtained in EXAMPLE 153 in 14 mlof DCM and 28 ml of TFA. After concentration of the reaction mixtureunder vacuum, the residue is taken up with DCM and the solvent isevaporated off under vacuum. The residue is taken up with iso ether and,after trituration, the solid formed is filtered off to give 1.9 g of theexpected product after crystallization from a DCM/iso ether mixture.M.p.=183° C.

EXAMPLE 198 3- (4-Aminobutyl)amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

A suspension of 0.82 g of the compound obtained in EXAMPLE 163 in 5 mlof DCM is cooled to +4° C. and 10 ml of TFA are added. The reactionmixture is stirred for 3 hours at +4° C. and concentrated under vacuum,the residue is taken up with DCM and the solvent is evaporated off undervacuum. The residue is taken up with a 5% solution of sodium carbonateand extracted with AcOEt, the organic phase is washed with a saturatedsolution of NaCl and with water and dried over sodium sulfate and thesolvent is evaporated off under vacuum to give 0.44 g of the expectedproduct after crystallization from a DCM/iso ether mixture. M.p.=259° C.

EXAMPLE 199 3- (5-Aminopentyl)amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-onetrifluoroacetate

A solution of 0.9 g of the compound obtained in EXAMPLE 165 in 5 ml ofDCM is cooled to 0° C. and 10 ml of TFA are added. The reaction mixtureis stirred for 5 hours at 0° C. and concentrated under vacuum. Theresidue is taken up with water, and AcOEt and solid potassium carbonateare added. The insoluble product present at the interphase is filteredoff. This insoluble product is dissolved in a DCM/MeOH mixture, theorganic phase is dried over sodium sulfate and the solvents areevaporated off under vacuum to give 0.155 g of the expected productafter crystallization and then recrystallization from an MeOH/iso ethermixture. M.p.=202°-204° C.

NMR spectrum at 200 MHz in DMSO-d₆

1.15 ppm:t:6H

1.25 to 1.7 ppm:m:6H

2.3 ppm:mt:2H

2.8 ppm:t:2H

3.3 to 3.5 ppm:m:5H

6.7 to 8.2 ppm:m:13H

8.85 ppm:s:1H

EXAMPLE 200 3-5-(Acetylamino)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

A solution of 0.034 g of acetyl chloride in 0.5 ml of DCM is added at RTto a solution of 0.276 g of the compound obtained in EXAMPLE 199, in theform of the free base, and 2 ml of pyridine in 2 ml of DCM and themixture is stirred for 1 hour. A further 0.034 g of acetyl chloride isadded and the reaction mixture is stirred for 30 minutes at RT andconcentrated under vacuum. The residue is taken up with AcOEt, theorganic phase is washed with water and with a saturated solution of NaCland dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a DCM/AcOEtmixture (50/50; v/v) as the eluent to give 0.14 g of the expectedproduct after crystallization from a DCM/iso ether mixture.M.p.=195°-198° C.

EXAMPLE 201 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-2-(piperazin-1-yl)ethyl!amino!indol-2-one

3.3 ml of trifluoromethanesulfonic acid are added at RT to a solution of1.2 g of the compound obtained in EXAMPLE 170 and 0.7 g of anisole in 24ml of TFA. The mixture is stirred for precisely 10 minutes, 35 ml ofether are added and the precipitate formed is filtered off. Theprecipitate is dissolved in an AcOEt/water mixture, sodium carbonate isadded to pH 10 and then, after decantation, the organic phase is washedwith water and dried over sodium sulfate and the solvent is evaporatedoff under vacuum. The residue is chromatographed on silica using aDCM/MeOH/triethylamine mixture (90/10/1; v/v/v) as the eluent to give0.825 g of the expected product after trituration in a DCM/iso ethermixture and then filtration. M.p.=260° C.

NMR spectrum at 200 MHz in DMSO-d₆

1.1 ppm:t:6H

2.0 to 2.8 ppm:m:12H

3.4 ppm:qd:4H

6.7 to 8.3 ppm:m:12H

8.8 ppm:s:1H

EXAMPLE 202 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-2-(4-methyl-piperazin-1-yl)ethyl!amino!indol-2-one

0.03 g of paraformaldehyde and 0.02 g of sodium cyanoborohydride areadded in portions in 4 hours to a solution of 0.16 g of the compoundobtained in EXAMPLE 201 in 4 ml of MeOH and 1 ml of AcOH. The mixture isstirred overnight at RT, 5 drops of concentrated HCl are added, water isthen added after 10 minutes and the reaction mixture is renderedalkaline by the addition of potassium carbonate. The organic solventsare concentrated under vacuum, the residue is extracted with DCM anddried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a DCM/MeOHmixture (88/12; v/v) as the eluent to give 0.099 g of the expectedproduct after crystallization from a DCM/hexane/iso ether mixture.

NMR spectrum at 200 MHz in DMSO-d₆

1.1 ppm:t:6H

1.9 to 3.6 ppm:m:19H

6.6 to 8.2 ppm:m:11H

8.8 ppm:s:1H

EXAMPLE 203

3- 4-(2-Aminoethyl)piperazin-1-yl!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-onemonohydrate

1.5 ml of trifluoromethanesulfonic acid are added at RT to a solution of0.7 g of the compound obtained in EXAMPLE 171 and 0.4 g of anisole in 15ml of TFA. The mixture is stirred for 12 minutes, ether is added and theprecipitate formed is filtered off. The precipitate is dissolved in anAcOEt/water mixture, potassium carbonate is added to pH 10 and then,after decantation, the organic phase is washed with water and with asaturated solution of NaCl and dried over sodium sulfate and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing a DCM/ MeOH/triethylamine mixture (90/10/1; v/v/v) as the eluent.The product obtained is dissolved in AcOEt, the organic phase is washedtwice with a 5% solution of potassium carbonate and dried over sodiumsulfate and the solvent is evaporated off under vacuum. The residue istaken up with a DCM/iso ether/hexane mixture, an insoluble material isfiltered off and the filtrate is concentrated under vacuum. The residueis taken up with a DCM/hexane mixture to give 0.192 g of the expectedproduct after trituration and then filtration.

NMR spectrum at 200 MHz in DMSO-d₆

1.1 ppm:t:6H

1.8 to 3.0 ppm:m:12H

3.3 ppm:qd:4H

6.6 to 8.1 ppm:m:11H

8.6 ppm:s:1H

EXAMPLE 204 3- (3-Carbamoylpropyl)amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one A) 4- N-5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-2,3-dihydro-2-oxoindol-3-yl!amino!butyricacid

A mixture of 0.78 ml of the compound obtained in EXAMPLE 180, 0.17 g of5% palladium-on-charcoal and 15 ml of AcOH is hydrogenolyzed atatmospheric pressure and at RT. After 30 minutes, the catalyst isfiltered off on Celite® and washed with AcOH and the filtrate isconcentrated under vacuum. The residue is taken up with iso ether and,after trituration, the precipitate formed is filtered off to give 0.67 gof the expected product, which is used as such.

B) 3- (3-Carbamoylpropyl)amino!-5-chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-one

A solution of 0.67 g of the compound obtained in the previous step in 10ml of DMF is cooled to 0° C., 0.467 g of BOP is added and the mixture isstirred for 15 minutes. 0.2 ml of a concentrated aqueous solution ofammonia is then added at 0° C. and the reaction mixture is stirred for18 hours, the temperature being allowed to rise to RT. It is poured intowater and extracted with AcOEt, the organic phase is washed with waterand dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed graphed on silica using aDCM/MeOH mixture (95/5; v/v) as the eluent to give 0.32 g of theexpected product after crystallization from a DCM/iso ether mixture.M.p.=192° C.

EXAMPLE 2055-Chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-1-(2,4-dimethoxybenzenesulfonyl)-3-(methylamino)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 1 from 0.25 g of5-chloro-3-(2-chlorophenyl)-7-fluoro-1,3-dihydro-3-(methylamino)indol-2-oneand 0.165 g of 2,4-dimethoxybenzenesulfonyl chloride. 0.075 g of theexpected product is obtained after crystallization and recrystallizationfrom a DCM/iso ether mixture. M.p.=183°-185° C.

EXAMPLE 206 3-(2-Chlorophenyl)-5-ethoxy-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(dimethylamino)indol-2-oneA)3-(2-Chlorophenyl)-5-ethoxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)-3-(dimethylamino)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 16 from 1 g of the compound obtained in Preparation 68 and 0.762g of 2-methoxy-4-nitrobenzenesulfonyl chloride. Chromatography on silicausing DCM and then a DCM/AcOEt mixture (90/10; v/v) as the eluent gives0.8 g of the expected product, which is used as such.

B)1-(4-Amino-2-methoxybenzenesulfonyl)-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydro-3-(dimethylamino)indol-2-one

This compound is prepared according to the procedure described in step Bof EXAMPLE 103 from 1.5 g of the compound obtained in the previous step.Chromatography on silica using DCM and then a DCM/AcOEt mixture (95/5;v/v) as the eluent gives 0.756 g of the expected product, which is usedas such.

C) 3-(2-Chlorophenyl)-5-ethoxy-1,3-dihydro-1-2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl!-3-(dimethylamino)indol-2-one

This compound is prepared according to the procedure described in step Aof EXAMPLE 27 from 0.756 g of the compound obtained in the previous stepand 0.22 ml of phenyl chloroformate. Chromatography on silica using DCMand then a DCM/AcOEt mixture (95/5; v/v) as the eluent gives 0.785 g ofthe expected product, which is used as such.

D) 3-(2-Chlorophenyl)-5-ethoxy-1-4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl!-1,3-dihydro-3-(dimethylamino)indol-2-one

This compound is prepared according to the procedure described in step Bof EXAMPLE 27 from 0.780 g of the compound obtained in the previous stepand 0.25 ml of diethylamine. 0.605 g of the expected product is obtainedafter crystallization from a DCM/iso ether mixture. M.p.=212°-214° C.

The compounds according to the invention collected in TABLE IV below areprepared from the 1,3-dihydroindol-2-ones described in the Preparationsand 4-(N',N'-diethylureido)benzenesulfonyl chloride by following theprocedure described in EXAMPLE 30.

                                      TABLE IV                                    __________________________________________________________________________     ##STR343##                                                                                                        Salt, solvate;                                                                M.p. °C. or NMR                                                        cristallization                          Example                                                                            R.sub.1                                                                           R.sub.2                                                                           R.sub.3 R.sub.4         solvent                                  __________________________________________________________________________    207  Me  H                                                                                  ##STR344##                                                                           NHMe            227-228 DCM/iso ether                    208  5-Et                                                                              H                                                                                  ##STR345##                                                                           NHMe            0.5 H.sub.2 O 230-231 DCM/iso ether      209  5-OMe                                                                             H                                                                                  ##STR346##                                                                           NH.sub.2        201 DCM/iso ether                        210  OEt H                                                                                  ##STR347##                                                                           NHEt            218-220 DCM/iso ether                    211  5-F H                                                                                  ##STR348##                                                                           NHMe            1 H.sub.2 O 195 DCM/iso ether            212  5-Cl                                                                              4-Me                                                                               ##STR349##                                                                           NHMe            236-239 DCM/iso ether                    213  5-Cl                                                                              6-Me                                                                               ##STR350##                                                                           NHMe            264 DCM/iso ether                        214  5-Cl                                                                              6-Me                                                                               ##STR351##                                                                            ##STR352##     0.5 THF 210-211 DCM/iso ether            215  5-Cl                                                                              6-Cl                                                                               ##STR353##                                                                            ##STR354##     0.25 DCM 203-205 DCM/iso ether           216  5-Cl                                                                              6-Cl                                                                               ##STR355##                                                                           NH(CH.sub.2).sub.3 OMe                                                                        202 DCM/iso ether                        217  5-Cl                                                                              6-Cl                                                                               ##STR356##                                                                            ##STR357##     119 DCM/iso ether                        218  5-Cl                                                                              6-Cl                                                                               ##STR358##                                                                            ##STR359##     155 DCM/iso ether/ hexane                219  5-Cl                                                                              6-Cl                                                                               ##STR360##                                                                           NH(CH.sub.2).sub.5 NHBoc                                                                      174 DCM/iso ether                        __________________________________________________________________________

EXAMPLE 220 5,6-Dichloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-2-(piperid-4-yl)ethyl!amino!indol-2-one 1.1 trifluoroacetate

A mixture of 1.4 g of the compound obtained in EXAMPLE 215, 15 ml of TFAand 5 ml of DCM is stirred for 2 hours 15 minutes at 0° C. and thereaction mixture is concentrated under vacuum. The residue is taken upwith ether and the solvent is evaporated off under vacuum, thisoperation being effected three times. The product obtained is dissolvedin AcOEt, iso ether is added, the solvent is evaporated off slowly andthe precipitate formed is filtered off and washed with iso ether to give0.95 g of the expected product. M.p.=158°-161° C.

EXAMPLE 221 3- (5-Aminopentyl)amino!-5,6-dichloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydroindol-2-onetrifluoroacetate

A solution of 0.8 g of the compound obtained in EXAMPLE 219 in 3 ml ofDCM is cooled to 0° C., 8.8 ml of TFA are added and the reaction mixtureis stirred for 2 hours. It is concentrated under vacuum and the residueis crystallized from a DCM/iso ether mixture to give 0.467 g of theexpected product. M.p.=195° C.

EXAMPLE 222 3-2-(1-tert-Butoxycarbonylpiperid-4-yl)-ethyl!amino!-5-chloro-3-(2-chlorophenyl)-1-1-(diethyethylaminocarbonyl)indolin-5-yl!sulfonyl!-1,3-dihydroindol-2-one

A solution of 1 g of 3-2-(1-tert-butoxycarbonylpiperid-4-yl)ethyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-onein 5 ml of DMF is cooled to +4° C. under an argon atmosphere and 0.087 gof sodium hydride as a 60% dispersion in oil is added. After stirringfor 30 minutes at +4° C., 0.627 g of1-(diethylaminocarbonyl)indoline-5-sulfonyl chloride is added and themixture is stirred for 3 hours at RT. 50 ml of water are added to thereaction mixture, extraction is carried out with AcOEt, the organicphase is washed with a saturated solution of NaCl and with water anddried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using DCM and then aDCM/AcOEt mixture (88/12; v/v) as the eluent to give 1.97 g of theexpected product after crystallization from a DCM/iso ether mixture.M.p.=139° C.

EXAMPLE 223 5-Chloro-3-(2-chlorophenyl)-1-1-(diethylaminocarbonyl)indolin-5-yl!sulfonyl!-1,3-dihydro-3-2-(piperid-4-yl)ethyl!amino!indol-2-one trifluoroacetate monohydrate

A solution of 1.17 g of the compound obtained in EXAMPLE 222 in 7.5 mlof DCM is cooled to +4° C., 15 ml of TFA are added and the reactionmixture is stirred for 3 hours 15 minutes at +4° C. It is concentratedunder vacuum, the residue is taken up with DCM and the solvent isevaporated off under vacuum, this operation being repeated twice. Theresidue is taken up with AcOEt, the organic phase is washed with waterand with a saturated solution of NaCl and dried over sodium sulfate andthe solvent is evaporated off under vacuum to give 0.6 g of the expectedproduct after trituration in iso ether and then crystallization from aDCM/iso ether mixture. M.p.=133° C.

EXAMPLE 224 1-(1-Acetylindolin-5-yl)sulfonyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(3-methoxypropyl)amino!indol-2-one hemihydrate

This compound is prepared according to the procedure described inEXAMPLE 222 from 1 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(3-methoxypropyl)amino!indol-2-one and 0.711 g of1-acetylindoline-5-sulfonyl chloride. 0.921 g of the expected product isobtained after crystallization from a DCM/iso ether mixture.M.p=158°-162° C.

EXAMPLE 225 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-1-1-(methoxycarbonyl)indolin-5-yl!sulfonyl!-3-(3-methoxypropyl)amino!indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 222 from 1.3 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(3-methoxypropyl)amino!indol-2-one and 0.980 g of1-(methoxycarbonyl)-indoline-5-sulfonyl chloride. 1.5 g of the expectedproduct are obtained after crystallization from a DCM/ iso ether/hexanemixture. M.p.=98° C.

EXAMPLE 226 3-(1S)-5-(Benzyloxycarbonylamino)-1-(hydroxymethyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-1-(diethylaminocarbonyl)indolin-5-yl!sulfonyl!-1,3-dihydroindol-2-one A)3- (1S)-5-(Benzyloxycarbonylamino)-1-(trimethylsilyloxy)methyl!pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-1-(diethylaminocarbonyl)indolin-5-yl!-sulfonyl!-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described inEXAMPLE 222 from the compound obtained in Preparation 60, 1.1 g of1-(diethylaminocarbonyl)indoline-5-sulfonyl chloride, 0.162 g of sodiumhydride as a 60% dispersion in oil and 20 ml of DMF. After stirring for4 hours at RT, the reaction mixture is poured into water and extractedwith AcOEt, the organic phase is washed with water and with a saturatedsolution of NaCl and dried over sodium sulfate and the solvent isevaporated off under vacuum to give the expected product in the form ofan oil, which is used as such.

B) 3-(1S)-5-(Benzyloxycarbonylamino)-1-(hydroxymethyl)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1-1-(diethylaminocarbonyl)indolin-5-yl!sulfonyl!-1,3-dihydroindol-2-one

A mixture of the compound obtained in the previous step, 30 ml of AcOH,10 ml of THF and 10 ml of water is stirred for 30 minutes at RT. Thereaction mixture is poured into water and extracted with AcOEt, theorganic phase is washed with water and with a 5% solution of sodiumhydrogencarbonate and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing a DCM/AcOEt mixture (60/40; v/v) as the eluent to give 0.23 g ofthe expected product in the form of a foam. α_(D) ²⁵ =+119.4° (c=0.25;chloroform).

EXAMPLE 227 5-Chloro-3-(2-chlorophenyl)-1-1-(diethylaminocarbonyl)indolin-5-yl!sulfonyl!-3-3-(diethylamino)propionamido!-1,3-dihydroindol-2-one, (+) isomer

This compound is prepared according to the procedure described inEXAMPLE 222 from 0.313 g of the compound obtained in Preparation 64, (+)isomer, and 0.21 g of 1-(diethylaminocarbonyl)indoline-5-sulfonylchloride. Chromatography on silica using a DCM/MeOH mixture (80/20; v/v)as the eluent gives 0.22 g of the expected product after crystallizationfrom a DCM/ hexane/iso ether mixture. M.p.=130°-133° C. α_(D) ²⁵ =+57.7°(c=0.21; chloroform).

The compounds according to the invention collected in TABLE V below areprepared from the 1,3-dihydroindol-2-ones described in the Preparationsand 1-(diethylaminocarbonyl)indoline-5-sulfonyl chloride by followingthe procedure described in EXAMPLE 222.

                                      TABLE V                                     __________________________________________________________________________     ##STR361##                                                                                                      Solvate;                                                                      M.p. °C. or NMR;                                                       cristallization                            Example                                                                            R.sub.1                                                                           R.sub.2                                                                          R.sub.3 R.sub.4        solvent                                    __________________________________________________________________________    228  5-Cl                                                                              H                                                                                 ##STR362##                                                                           NH(CH.sub.2).sub.3 OMe                                                                       148-152 DCM/iso ether                      229  5-Cl                                                                              H                                                                                 ##STR363##                                                                            ##STR364##    NMR                                        230  5-Cl                                                                              H                                                                                 ##STR365##                                                                           NH(CH.sub.2).sub.5 NHBoc                                                                     0.25 iso ether 148 DCM/iso ether           231  5-Cl                                                                              H                                                                                 ##STR366##                                                                            ##STR367##    130 DCM/iso ether                          232  5-Cl                                                                              H                                                                                 ##STR368##                                                                            ##STR369##    175 DCM/iso ether                          233  5-Cl                                                                              H                                                                                 ##STR370##                                                                            ##STR371##    145 DCM/iso ether                          234  5-Cl                                                                              H                                                                                 ##STR372##                                                                            ##STR373##    NMR                                        235  5-Cl                                                                              H                                                                                 ##STR374##                                                                            ##STR375##    187 DCM/iso ether                          236  5-Cl                                                                              H                                                                                 ##STR376##                                                                           NH(CH.sub.2).sub.4 COOBz                                                                     122-123 DCM/iso ether                      237  5-Cl                                                                              H                                                                                 ##STR377##                                                                           NH(CH.sub.2).sub.5 COOBz                                                                     101-102 DCM/iso ether                      __________________________________________________________________________

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 229

0.95 ppm:t:6H

1.2 ppm:t:6H

2.1 to 2.6 ppm:m:8H

3.15 ppm:t:2H

3.3 ppm:qd:4H

3.9 ppm:t:2H

6.8 to 8.2 ppm:m:10H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 234

1.05 ppm:t:6H

1.3 ppm:s:9H

2.2 ppm:s:3H

2.95 ppm:t:2H

3.05 to 3.3 ppm:m:8H

3.85 ppm:t:2H

6.8 to 7.8 ppm:m:10H

EXAMPLE 238 3- (5-Aminopentyl)amino!-5-chloro-3-(2-chlorophenyl)-1-1-(diethylaminocarbonyl)indolin-5-yl!sulfonyl!-1,3-dihydroindol-2-onetrifluoroacetate

A solution of 0.83 g of the compound obtained in EXAMPLE 230 in 5 ml ofDCM is cooled to 0° C. 10 ml of TFA are added and the reaction mixtureis stirred for 5 hours at +4° C. It is concentrated in the cold undervacuum, the residue is taken up with DCM and the solvent is evaporatedoff under vacuum. The residue is taken up with a 5% solution of sodiumcarbonate and extracted with AcOEt, the organic phase is washed with asaturated solution of NaCl and with water and dried over sodium sulfateand the solvent is evaporated off under vacuum to give 0.150 g of theexpected product after crystallization from iso ether. M.p.=200° C.

EXAMPLE 239 3- 2-N-(Carboxymethyl)-N-methylamino!acetamido!-5-chloro-3-(2-chlorophenyl)-1-l-(diethylamino-carbonyl)indolin-5-yl!sulfonyl!-1,3-dihydroindol-2-onetrifluoroacetate hemihydrate

12 ml of TFA are added to a solution of 2.5 g of the compound obtainedin EXAMPLE 234 in 12 ml of DCM and the mixture is stirred for 3 hours atRT. It is concentrated under vacuum at 35° C., the residue is taken upwith ether and the precipitate formed is filtered off and washed withether to give 2.2 g of the expected compound.

NMR spectrum at 200 MHz in DMSO-d₆

1.2 ppm:t:6H

2.8 ppm:s:3H

3.15 ppm:t:2H P1 3.35 ppm:qd:4H

3.8 to 4.2 ppm:m:6H

7.0 to 8.0 ppm:m:10H

10.0 ppm:s:1H

EXAMPLE 240 5-Chloro-3-(2-chlorophenyl)-1-1-(diethylaminocarbonyl)indolin-5-yl!sulfonyl!-1,3-dihydro-3-(piperid-4-yl)methyl!amino!indol-2-one trifluoroacetate hemihydrate

A solution of 1.5 g of the compound obtained in EXAMPLE 235 in 12 ml ofDCM is cooled to 0° C. 12 ml of TFA are added and the mixture is stirredfor 3 hours at 0° C. It is concentrated under vacuum at 30° C., theresidue is taken up with iso ether and the precipitate formed isfiltered off and washed with iso ether to give 1.36 g of the expectedproduct.

NMR spectrum at 200 MHz in DMSO-d₆

0.8 to 2.4 ppm:m:13H

2.6 to 3.4 ppm:m:10H

3.9 ppm:t:2H

6.6 to 8.8 ppm:m:12H

EXAMPLE 241 1-4-(N-tert-Butylcarbamoyl)benzyl!-5-chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydroindol-2-oneA) tert-Butyl 4-5-chloro-3-(2-chlorophenyl)-3-(ethylamino)-2,3-dihydro-2-oxoindol-1-yl!methyl!benzoate

This compound is prepared according to the procedure described in step Aof EXAMPLE 96 from 1.19 g of5-chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydroindol-2-one and1.1 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silicausing a gradient of a hexane/AcOEt mixture (from 95/5; v/v to 90/10;v/v) as the eluent gives 0.9 g of the expected product, which is used assuch.

B) 4-5-Chloro-3-(2-chlorophenyl)-3-(ethylamino)-2,3-dihydro-2-oxoindol-1-yl!methyl!benzoicacid

This compound is prepared according to the procedure described in step Bof EXAMPLE 96 from 0.4 g of the compound obtained in the previous step.This gives the expected product, which is used as such.

C) 1-4-(N-tert-Butylcarbamoyl)benzyl!-5-chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydroindol-2-one

A solution of the compound obtained in the previous step in 4 ml of DCMis cooled to 0° C. and 0.14 ml of DIPEA and then 0.25 ml oftert-butylamine and 0.345 g of BOP are added. The reaction mixture isstirred for 3 hours at RT and concentrated under vacuum. The residue istaken up with AcOEt, the organic phase is washed with a 5% solution ofpotassium carbonate, with water and with a saturated solution of NaCland dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a gradient of ahexane/AcOEt mixture (from 90/10; v/v to 50/50; v/v) as the eluent togive 0.28 g of the expected product after crystallization from a DCM/isoether mixture. M.p.=190°-195° C.

EXAMPLE 242 5-Chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydro-1- 4-N-(2-hydroxy-1,1-dimethylethyl)carbamoyl!benzyl!indol-2-one 0.1 H₂ O

A solution of 0.374 g of the compound obtained in step B of EXAMPLE 241in 5 ml of DCM is cooled to 0° C. and 0.34 ml of triethylamine and then0.16 ml of 2-amino-2-methylpropan-1-ol and 0.364 g of BOP are added. Thereaction mixture is stirred for 1 hour at RT and concentrated undervacuum. The residue is taken up with AcOEt, the organic phase is washedwith water, with a 5% solution of potassium carbonate and with asaturated solution of NaCl and dried over sodium sulfate and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/AcOEt mixture (70/30; v/v) as the eluent togive 0.3 g of the expected product after crystallization from a DCM/isoether mixture. M.p.=170°-172° C.

NMR spectrum at 200 MHz in DMSO-d₆

1.1 ppm:t:3H

1.35 ppm:s:6H

2.4 ppm:mt:2H

3.25 ppm:t:1H

3.75 ppm:d:2H

4.95 ppm:t:1H

5.05 ppm:AB system:2H

6.7 to 8.4 ppm:m:11H

EXAMPLE 243 5-Chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydro-1- 4-N- 1,1-di(hydroxymethyl)ethyl!carbamoyl!-benzyl!indol-2-one

A solution of 0.172 g of 2-amino-2-methylpropane-1,3-diol in 2 ml of DMFis added at RT to a mixture of 0.374 g of the compound obtained in stepB of EXAMPLE 241, 0.25 g of triethylamine, 0.364 g of BOP and 5 ml ofDCM and the reaction mixture is stirred for 3 hours at RT. It isconcentrated under vacuum, the residue is taken up with water andextracted with AcOEt, the organic phase is washed twice with a 5%solution of potassium carbonate, with water and with a saturatedsolution of NaCl and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing an AcOEt/DCM mixture (80/20; v/v) as the eluent to give 0.18 g ofthe expected product after crystallization from a DCM/iso ether mixture.M.p.=138°-141° C.

EXAMPLE 244 1-4-(N-tert-Butylcarbamoyl)benzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one,(+) isomer A) tert-Butyl 4-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-3-(dimethylamino)-2-oxoindol-1-yl!methyl!-benzoate

This compound is prepared according to the procedure described inEXAMPLE 93 from 0.62 g of the compound obtained in Preparation 76, (+)isomer, 0.085 g of sodium hydride as a 60% dispersion in oil and 0.555 gof tert-butyl 4-bromomethylbenzoate. Chromatography on silica using aDCM/AcOEt mixture (95/5; v/v) as the eluent gives 0.662 g of theexpected product in the form of an oil, which is used as such.

B) 4-5-Chloro-3-(2-chlorophenyl)-2,3-dihydro-3-(dimethylamino)-2-oxoindol-1-yl!methyl!benzoicacid

This compound is prepared according to the procedure described in step Aof EXAMPLE 94 from 0.662 g of the compound obtained in the previousstep. The expected product is obtained in the form of an oil, which isused as such.

C) 1-4-(N-tert-Butylcarbamoyl)benzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one,(+) isomer

0.4 g of triethylamine is added to a solution of the compound obtainedin the previous step in 5 ml of DCM to bring the pH to 7 and 0.14 g oftert-butylamine and 0.564 g of BOP are then added. The mixture isstirred for 48 hours at RT, a pH of 7 being maintained by the additionof triethylamine. The mixture is concentrated under vacuum, the residueis taken up with a 5% solution of potassium carbonate and extracted withAcOEt, the organic phase is washed with water and with a saturatedsolution of NaCl and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing a DCM/ AcOEt mixture (92/8; v/v) as the eluent to give 0.225 g ofthe expected product after crystallization from a DCM/hexane mixture.M.p.=177°-178° C. α_(D) ²⁵ =+148.6° (c=0.17; chloroform).

EXAMPLE 2455-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)-1-(4-nitrobenzyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 89 from 1 g of5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one,0.132 g of sodium hydride as a 60% dispersion in oil, 5 ml of DMF and0.741 g of 4-nitrobenzyl bromide. Chromatography on silica using aDCM/hexane mixture (80/20; v/v) and then DCM as the eluent gives 1.32 gof the expected product after crystallization from a DCM/ iso ethermixture. M.p.=189°-193° C.

EXAMPLE 246 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzyl!-1,3-dihydro-3-(dimethylamino)indol-2-oneA)1-(4-Aminobenzyl)-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)indol-2-one

A mixture of 1.88 g of the compound obtained in EXAMPLE 245, 0.9 g ofRaney® nickel, 40 ml of MeOH and 40 ml of THF is hydrogenated atatmospheric pressure for 2 hours at RT. The catalyst is filtered off onCelite® and the filtrate is evaporated under vacuum. The residue ischromatographed on silica using DCM and then a DCM/AcOEt mixture (95/5;v/v) as the eluent to give 1.58 g of the expected product, which is usedas such.

B) 5-Chloro-3-(2-chlorophenyl)-1,3-dihydro-3-(dimethylamino)-1-4-(phenoxycarboxamido)benzyl!indol-2-one

A solution of 1 g of the compound obtained in the previous step in 5 mlof pyridine is cooled to 0° C., 0.31 ml of phenyl chloroformate is addedand the mixture is stirred for 2 hours at RT. Water is added to thereaction mixture, extraction is carried out with AcoEt, the organicphase is washed with water and with a saturated solution of NaCl anddried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using DCM and then aDCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.98 g of theexpected product, which is used as such.

C) 5-Chloro-3-(2-chlorophenyl)-1-4-(N',N'-diethylureido)benzyl!-1,3-dihydro-3-(dimethylamino)indol-2-one

A mixture of 0.45 g of the compound obtained in the previous step, 0.17ml of diethylamine and 5 ml of chloroform is heated at 60° C. for 4hours. The reaction mixture is concentrated under vacuum and the residueis chromatographed on silica using DCM and then a DCM/ AcOEt mixture(95/5; v/v) as the eluent to give 0.37 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=193°-198° C.

EXAMPLE 247 3-5-(tert-Butoxycarbonylamino)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-2-methoxy-4-(N,N-dimethylcarbamoyl)benzyl!indol-2-one hemihydrate A)Methyl 4- 3-5-(tert-butoxycarbonylamino)pentyl!-amino!-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!methyl!-3-methoxybenzoate

This compound is prepared according to the procedure described inEXAMPLE 89 from 2 g of 3-5-(tert-butoxycarbonylamino)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-oneand 1.19 g of methyl 4-bromomethyl-3-methoxybenzoate. 2.06 g of theexpected product are obtained.

NMR spectrum at 200 MHz in DMSO-d₆

1.10 to 1.65 ppm:m:15H

2.35 ppm:mt:2H

3.2 ppm:t:1H

3.9 ppm:s:3H

4.0 ppm:s:3H

5.0 ppm:AB system:2H

6.8 ppm:t:1H

6.85 to 8.3 ppm:m:10H

B) 4- 3-5-(tert-Butoxycarbonylamino)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxoindol-1-yl!methyl!-3-methoxybenzoicacid

A solution of 0.375 g of lithium hydroxide monohydrate in 3 ml of wateris added at RT to a solution of 1.95 g of the compound obtained in theprevious step in 9.4 ml of 1,4-dioxane and the mixture is stirred for 4days at RT. Water is added to the reaction mixture, which is neutralizedto pH 7 by the addition of 1N HCl, the 1,4-dioxane is evaporated offunder vacuum and the aqueous phase is acidified to pH 1 by the additionof 1N HCl. Extraction is carried out with AcOEt, the organic phase iswashed with water and with a saturated solution of NaCl and dried oversodium sulfate and the solvent is evaporated off under vacuum to give 2g of the expected product, which is used as such.

C) 3-5-(tert-Butoxycarbonylamino)pentyl!amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-2-methoxy-4-(N,N-dimethylcarbamoyl)benzyl!indol-2-one hemihydrate

A solution of 1 g of the compound obtained in the previous step in 10 mlof DCM is cooled to 0° C. and 0.3 ml of DIPEA and then 0.13 ml ofdimethylamine and 0.69 g of BOP are added. The mixture is stirred for 12hours at RT and concentrated under vacuum. The residue is extracted withAcOEt, the organic phase is washed with water and with a saturatedsolution of NaCl and dried over sodium sulfate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing DCM and then a DCM/AcOEt mixture (80/20; v/v) as the eluent togive 0.54 g of the expected product after crystallization from a DCM/isoether mixture. M.p.=75°-80° C.

EXAMPLE 248 3-(5-Aminopentyl)amino!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-1-2-methoxy-4-(N,N-dimethylcarbamoyl)benzyl!indol-2-one ditrifluoroacetatemonohydrate

A solution of 0.1 g of the compound obtained in EXAMPLE 247 in 1 ml ofDCM is cooled to 0° C., 1.3 ml of TFA are added and the reaction mixtureis stirred for 2 hours at 0° C. It is concentrated under vacuum, theresidue is taken up with DCM and the solvent is evaporated off undervacuum to give 0.07 g of the expected product after crystallization andrecrystallization from a DCM/iso ether mixture. M.p.=178°-180° C.

EXAMPLE 249 3- (5-Aminopentyl)amino!-1-4-(N-tert-butylcarbamoyl)-2-methoxybenzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one1.5 trifluoroacetate 1.5 hydrate A) 3-5-(tert-Butoxycarbonylamino)pentyl!amino!-1-4-(N-tert-butylcarbamoyl)-2-methoxybenzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one

This compound is prepared according to the procedure described in step Cof EXAMPLE 247 from 1.2 g of the compound obtained in step B of EXAMPLE247, 0.33 ml of DIPEA, 0.6 ml of tert-butylamine and 0.827 g of BOP.Chromatography on silica using DCM and then a DCM/AcOEt mixture (90/10;v/v) as the eluent gives 0.685 g of the expected product, which is usedas such.

B) 3- (5-Aminopentyl)amino!-1-4-(N-tert-butylcarbamoyl)-2-methoxybenzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one1.5 trifluoroacetate 1.5 hydrate

A solution of 0.52 g of the compound obtained in the previous step in 2ml of DCM is cooled to 0° C., 6.3 ml of TFA are added and the mixture isstirred for 2 hours at 0° C. It is concentrated under vacuum, theresidue is taken up with DCM and the solvent is evaporated off undervacuum to give 0.3 g of the expected product after crystallization andrecrystallization from a DCM/iso ether mixture. M.p.=138°-140° C.

EXAMPLE 250 1-4-(N-tert-Butylcarbamoyl)-2-methoxybenzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-propionamidoindol-2-oneA) Methyl 4-5-chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxo-3-propionamidoindol-1-yl!methyl!-3-methoxybenzoate

0.52 g of propionyl chloride is added at RT to a solution of 1.323 g ofthe compound obtained in EXAMPLE 89 in 5 ml of pyridine and the mixtureis stirred for 24 hours. It is concentrated under vacuum, the residue isextracted with AcOEt, the organic phase is washed with water and with asaturated solution of NaCl and dried over sodium sulfate and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing a DCM/AcOEt mixture (90/10; v/v) as the eluent to give 1.3 g ofthe expected product.

B) 4-5-Chloro-3-(2-chlorophenyl)-2,3-dihydro-2-oxo-3-propionamidoindol-1-yl!methyl!-3-methoxybenzoicacid

0.24 g of lithium hydroxide monohydrate is added at RT to a mixture of1.3 g of the compound obtained in the previous step, 5 ml of1,4-dioxane, 2 ml of MeOH and 2 ml of water and the reaction medium isstirred for 24 hours. It is acidified to pH 1 by the addition ofconcentrated HCl and the solvents are evaporated off under vacuum. Theresidue is taken up with water and extracted with AcOEt, the organicphase is washed with water and with a saturated solution of NaCl anddried over sodium sulfate and the solvent is evaporated off under vacuumto give 1.342 g of the expected product, which is used as such.

C) 1-4-(N-tert-Butylcarbamoyl)-2-methoxybenzyl!-5-chloro-3-(2-chlorophenyl)-1,3-dihydro-3-propionamidoindol-2-one

0.22 g of DIPEA and then 0.382 g of BOP and 0.185 g of tert-butylamineare added at RT to a solution of 0.432 g of the compound obtained in theprevious step in 7 ml of DCM and the mixture is stirred for 1 hour atRT. It is concentrated under vacuum, the residue is extracted withAcOEt, the organic phase is washed three times with a 5% solution ofpotassium carbonate, with water and with a saturated solution of NaCland dried over sodium sulfate and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using a DCM/AcOEtmixture (65/35; v/v) as the eluent to give 0.303 g of the expectedproduct after crystallization from a DCM/iso ether mixture. M.p.=249° C.

The compounds according to the invention collected in TABLE VI below areprepared from the 1,3-dihydroindol-2-ones described in the Preparationsby following the procedures described in the EXAMPLES above.

                                      TABLE VI                                    __________________________________________________________________________     ##STR378##                                                                                                         Solvate;                                                                      M.p. °C. or                                                            NMR;                                                                          cristallization                         Example                                                                            R.sub.3  R.sub.4 R.sub.5                                                                           R.sub.6     solvent                                 __________________________________________________________________________    251 (a)                                                                             ##STR379##                                                                             ##STR380##                                                                           H                                                                                  ##STR381## 115-120 DCM/iso ether                   252 (b)                                                                             ##STR382##                                                                            NHCOEt  2-OMe                                                                              ##STR383## 177-178 DCM/iso ether                   253 (c)                                                                             ##STR384##                                                                            NH.sub.2                                                                              H   4-NO.sub.2  172 DCM/iso ether                       254 (d)                                                                             ##STR385##                                                                            NHCOOMe H   4-NO.sub.2  203 DCM/iso ether                       255 (e)                                                                             ##STR386##                                                                            NHCOOMe H   4-NH.sub.2  225 DCM/iso ether                       256 (f)                                                                             ##STR387##                                                                            NHCOOMe H                                                                                  ##STR388## 217 DCM/iso ether                       257 (g)                                                                             ##STR389##                                                                            NH.sub.2                                                                              H                                                                                  ##STR390## 150 DCM/iso ether                       258 (h)                                                                             ##STR391##                                                                            NH.sub.2                                                                              2-OMe                                                                             4-CO.sub.2 Me                                                                             NMR                                     259 (d)                                                                             ##STR392##                                                                            NHCOOMe 2-OMe                                                                             4-CO.sub.2 Me                                                                             used as such                            260 (i)                                                                             ##STR393##                                                                            NHCOOMe 2-OMe                                                                             4-CONH-tBu  203 DCM/iso ether                       261 (j)                                                                             ##STR394##                                                                            NH.sub.2                                                                              2-OMe                                                                             4-CONH-tBu  0.25 H.sub.2 O 210 DCM/iso              __________________________________________________________________________                                          ether                               

(a) Compound prepared according to the procedure described in step C ofEXAMPLE 246 by using the appropriate amines.

(b) Compound prepared according to the procedure described in step C ofEXAMPLE 250 by using 2-amino-1-(diethylamino)-2-methylpropanedihydrochloride (synthesized according to J. Am. Chem. Soc., 1946, 68,12-14).

(c) Compound prepared according to the procedure described in EXAMPLE245.

(d) Compound prepared according to the procedure described in EXAMPLE90.

(e) Compound prepared according to the procedure described in step A ofEXAMPLE 246 from the compound obtained in EXAMPLE 254.

(f) Compound prepared according to the procedures described in step Band then step C of EXAMPLE 246.

(g) Compound prepared according to the procedure described in EXAMPLE 92from the compound obtained in EXAMPLE 256.

(h) Compound prepared according to the procedure described in EXAMPLE89.

(i) Compound prepared according to the procedures described in step Band then step C of EXAMPLE 250 from the compound obtained in EXAMPLE259.

(j) Compound prepared according to the procedure described in EXAMPLE 92from the compound obtained in EXAMPLE 260.

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 258

2.65 ppm:s:2H

3.3 ppm:s:3H

3.8 ppm:s:3H

3.95 ppm:s:3H

4.95 ppm:AB system:2H

6.7 to 8.1 ppm:m:10H

EXAMPLE 262 3-Amino-1-4-(N-tert-butylcarbamoyl)benzyl!-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-onehemihydrate A) tert-Butyl 4-3-amino-3-(2-chlorophenyl)-5-ethoxy-2,3-dihydro-2-oxoindol-1-yl!methyl!benzoate

This compound is prepared according to the procedure described inEXAMPLE 93 from 1 g of3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 0.984 gof tert-butyl 4-bromomethylbenzoate. Chromatography on silica using DCMand then a DCM/AcOEt mixture (70/30; v/v) as the eluent gives 1.053 g ofthe expected product.

NMR spectrum at 200 MHz in DMSO-d₆

1.2 ppm:t:3H

1.55 ppm:s:9H

2.8 ppm:s:2H

3.85 ppm:qd:2H

5.0 ppm:AB system:2H

6.3 to 8.4 ppm:m:11H

B) 4-3-Amino-3-(2-chlorophenyl)-5-ethoxy-2,3-dihydro-2-oxoindol-1-yl!methyl!benzoicacid

This compound is prepared according to the procedure described in step Aof EXAMPLE 94 from 1 g of the compound obtained in the previous step.This gives 0.9 g of the expected product, which is used as such.

C) 3-Amino-1-4-(N-tert-butylcarbamoyl)benzyl!-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-onehemihydrate

This compound is prepared according to the procedure described in step Cof EXAMPLE 241 from 0.4 g of the compound obtained in the previous step,0.16 ml of DIPEA, 0.29 ml of tert-butylamine and 0.405 g of BOP.Chromatography on silica using DCM and then a DCM/AcOEt mixture (70/30;v/v) as the eluent gives 0.161 g of the expected product aftercrystallization from a DCM/iso ether mixture. M.p.=208°-210° C.

EXAMPLE 263 3-Amino-3-(2-chlorophenyl)-5-ethoxy-1- 4- N-2-(diethylamino)-1,1-dimethylethyl!carbamoyl!benzyl!-1,3-dihydroindol-2-one

A solution of 0.896 g of the compound obtained in step B of EXAMPLE 262in 10 ml of DCM is cooled to 0° C. and 0.36 ml of DIPEA is added,followed by 0.445 g of 2-amino-1-(diethylamino)-2-methylpropanedihydrochloride and then by 1.14 ml of triethylamine and 0.906 g of BOP.The mixture is stirred for 1 hour at RT and concentrated under vacuum.The residue is taken up with AcOEt, the organic phase is washed with a5% solution of potassium carbonate, with water and with a saturatedsolution of NaCl and dried over sodium sulfate fate and the solvent isevaporated off under vacuum. The residue is chromatographed on silicausing AcOEt and then an AcOEt/MeOH mixture (80/20; v/v) as the eluent togive 0.12 g of the expected product after crystallization from aDCM/hexane mixture. M.p.=59° C.

The compounds according to the invention collected in TABLE VII beloware prepared from the 1,3-the procedures described in the EXAMPLESabove.

                                      TABLE VII                                   __________________________________________________________________________     ##STR395##                                                                                                                Salt, Solvate;                                                                M.p. °C. or                                                            NMR;                                                                          cristallization                  Example                                                                            R.sub.2                                                                           R.sub.4          X   R.sub.5                                                                           R.sub.6    solvent                          __________________________________________________________________________    264 (a)                                                                            H   NHMe             SO.sub.2                                                                          OMe                                                                                ##STR396##                                                                              NMR                              265 (b)                                                                            H                                                                                  ##STR397##      SO.sub.2                                                                          H                                                                                  ##STR398##                                                                              169-171 DCM/iso ether            266 (c)                                                                            H                                                                                  ##STR399##      SO.sub.2                                                                          H                                                                                  ##STR400##                                                                              132-134                          267 (d)                                                                            H                                                                                  ##STR401##      SO.sub.2                                                                          H                                                                                  ##STR402##                                                                              153-154 DCM/iso ether            268 (e)                                                                            H                                                                                  ##STR403##      SO.sub.2                                                                          H                                                                                  ##STR404##                                                                              1TFA, 2H.sub.2 O 163-164                                                      MeOH/iso ether                   269 (f)                                                                            H                                                                                  ##STR405##      SO.sub.2                                                                          H                                                                                  ##STR406##                                                                              --                               270 (g)                                                                            H                                                                                  ##STR407##      SO.sub.2                                                                          H                                                                                  ##STR408##                                                                              --                               271 (d)                                                                            4-Cl                                                                               ##STR409##      SO.sub.2                                                                          H                                                                                  ##STR410##                                                                              234                              272 (h)                                                                            4-Cl                                                                               ##STR411##      SO.sub.2                                                                          H                                                                                  ##STR412##                                                                              1TFA 175                         273 (d)                                                                            6-Cl                                                                               ##STR413##      SO.sub.2                                                                          H                                                                                  ##STR414##                                                                              220                              274 (i)                                                                            6-Cl                                                                               ##STR415##      SO.sub.2                                                                          H                                                                                  ##STR416##                                                                              1TFA 190                         275 (d)                                                                            6-Me                                                                               ##STR417##      SO.sub.2                                                                          H                                                                                  ##STR418##                                                                              264 DCM/iso ether                276 (j)                                                                            6-Me                                                                               ##STR419##      SO.sub.2                                                                          H                                                                                  ##STR420##                                                                              1TFA 180                         277 (k)                                                                            6-Me                                                                               ##STR421##      SO.sub.2                                                                          H                                                                                  ##STR422##                                                                              NMR                              278 (l)                                                                            H   NH.sub.2         CH.sub.2                                                                          H   COOtBu     --                               279 (m)                                                                            H   NH.sub.2         CH.sub.2                                                                          H   CONHtBu    0,5 H.sub.2 O                    280 (d)                                                                            H   NH(CH.sub.2).sub.2 SEt                                                                         SO.sub.2                                                                          H                                                                                  ##STR423##                                                                              197 DCM/iso                      __________________________________________________________________________                                                 ether                        

(a) Compound prepared according to the procedure described in step C ofEXAMPLE 112 from the compound obtained in step B of EXAMPLE 112 by usingthe appropriate amines.

(b) Compound prepared by hydrogenating the compound obtained in EXAMPLE148 at atmospheric pressure and at RT, in the presence of Raney® nickel.

(c) Compound prepared by reacting the compound obtained in EXAMPLE 265with paraformaldehyde, in the presence of sodium cyanoborohydride,according to the method described in EXAMPLE 34.

(d) Compound prepared according to the procedure described in EXAMPLE30.

(e) Compound prepared according to the procedure described in EXAMPLE198 from the compound obtained in EXAMPLE 175.

(f) Compound prepared according to the procedure described in EXAMPLE 30from the compound obtained in Preparation 111.

(g) Compound prepared according to the procedures described in steps A,B and then C of EXAMPLE 121 from the compound obtained in EXAMPLE 269.

(h) Compound prepared according to the procedure described in EXAMPLE193 from the compound obtained in EXAMPLE 271.

(i) Compound prepared according to the procedure described in EXAMPLE193 from the compound obtained in EXAMPLE 273.

(j) Compound prepared according to the procedure described in EXAMPLE193 from the compound obtained in EXAMPLE 275.

(k) Compound prepared according to the procedure described in EXAMPLE220 from the compound obtained in EXAMPLE 214.

(l) (+) isomer; compound prepared according to the procedure describedin step A of EXAMPLE 96 from the compound obtained in Preparation 28,(+) isomer. α_(D) ²⁵ =+148.8° (c=0.38; chloroform).

(m) (+) isomer; compound prepared according to the procedures describedin step B and then step C of EXAMPLE 96 from the compound obtained inEXAMPLE 278. α_(D) ²⁵ =+91.7° (c=0.218; chloroform).

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 264

1.3 ppm:s:6H

1.95 ppm:d:3H

2.1 to 2.8 ppm:m:6H

3.5 ppm:qd:1H

3.61 ppm:s:3H

6.6 to 8.2 ppm:m:11H

NMR spectrum at 200 MHz in DMSO-d₆ of the compound of EXAMPLE 277

0.8 to 1.8 ppm:m:13H

2.2 to 2.5 ppm:m:5H

2.6 to 3.3 ppm :m:4H

3.4 ppm:qd:4H

6.8 to 8.1 ppm:m:10H

The compounds according to the invention collected in TABLE VIII beloware prepared by following the procedures described in the EXAMPLESabove.

                                      TABLE VIII                                  __________________________________________________________________________     ##STR424##                                                                                                       Salt, Solvate                                                                 M.p. °C. or                                                            NMR;                                                                          cristallization                           Example                                                                            R.sub.1                                                                           R.sub.2                                                                           R.sub.3 R.sub.4        solvent                                   __________________________________________________________________________    281 (a)                                                                            5-Cl                                                                              H                                                                                  ##STR425##                                                                            ##STR426##    190 DCM/iso ether                         282 (b)                                                                            5-Cl                                                                              H                                                                                  ##STR427##                                                                            ##STR428##    1TFA 232 ether                            283 (c)                                                                            5-Cl                                                                              H                                                                                  ##STR429##                                                                           NH(CH.sub.2).sub.5 COOH                                                                      1H.sub.2 O, 0.25 iso ether 126-127                                            DCM/iso ether                             284 (d)                                                                            5-Cl                                                                              H                                                                                  ##STR430##                                                                           NH(CH.sub.2).sub.5 CONH.sub.2                                                                --                                        285 (a)                                                                            5-Cl                                                                              6-Cl                                                                               ##STR431##                                                                            ##STR432##    --                                        286 (e)                                                                            5-Cl                                                                              6-Cl                                                                               ##STR433##                                                                            ##STR434##    1TFA --                                   __________________________________________________________________________

(a) Compound prepared according to the procedure described in EXAMPLE222.

(b) Compound prepared according to the procedure described in EXAMPLE198 from the compound obtained in EXAMPLE 281.

(c) Compound prepared by hydrogenating the compound of EXAMPLE 237 atatmospheric pressure and at RT, in the presence of 5%palladium-on-charcoal in AcOH.

(d) Compound prepared by reacting the compound obtained in EXAMPLE 283with concentrated aqueous ammonia in the presence of BOP and DIPEA.

(e) Compound prepared according to the procedure described in EXAMPLE193 from the compound obtained in EXAMPLE 285.

EXAMPLE 287 3-(2-Chlorophenyl)-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-3-(methylamino)-5-(trifluoromethyl)indol-2-one

This compound is prepared according to the procedure described inEXAMPLE 30 from the compound obtained in Preparation 112. M.p.=233°-236°C.

EXAMPLE 288 5-chloro-3-(2-chlorophenyl)-3-3-(diethylamino)propionamido!-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-4-methylindol-2-one.

This compound is prepared according to the procedure described inEXAMPLE 30 from the compound obtained in Preparation 114. M.p.=208°-210°C.

EXAMPLE 289 5-chloro-3-(2-chlorophenyl)-3-3-(diethylamino)propionamido!-1-4-(N',N'-diethylureido)benzenesulfonyl!-1,3-dihydro-6-methylindol-2-one.

This compound is prepared according to the procedure described inEXAMPLE 30 from the compound obtained in Preparation 115.

NMR spectrum at 200 MHz in DMSO d₆

0.65 to 1.15 ppm:m:12H

2to 2.7 ppm:m:8H

3.1 to 3.5 ppm:m:4H

7 to 8 ppm:m:10H

8.65 ppm:s:1H

9.55 ppm:s:1H

What is claimed is:
 1. A compound of formula (II') ##STR435## in which:R_(I) and R_(II) are each independently a hydrogen, a halogen, a (C₁-C₇)alkyl, a (C₁ -C₇)alkoxy, a trifluoromethyl, a nitro, an amino, ahydroxyl or a benzyloxy, with the proviso that R_(I) and R_(II) are notsimultaneously hydrogen;R_(III) is a phenyl monosubstituted orpolysubstituted by a halogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁-C₇)alkoxy, a benzyloxy or an acetoxy; R_(IV) is an azido, an amino, a2,2-dimethylhydrazino group, a group NR₇ R₈, a group NR₉ R₁₀ or NR₉R_(XI), a heterocyclic radical R₁₂ or a piperazin-1-yl radicalsubstituted in the 4-position by a (C₂ -C₁₀)alkylene group substitutedby an amino group which is free or carries a protective group; R_(XI) isa (C₃ -C₇)cycloalkylmethyl, a group OR₁₃, a group CH₂ R₃₆ or a groupω-R₃₂ R₃₃ N(C₁ -C₄)alkylcarbonyl; and R₇ is a (C₁ -C₇)alkoxycarbonylgroup; R₈ is a (C₁₋ C₇)alkoxycarbonylamino group; or an N-methyl-N-(C₁-C₇)alkoxycarbonylamino group; R₉ is a hydrogen atom; or a (C₁ -C₇)alkylgroup; R₁₀ is a group CR₁₈ R₁₉ R₂₀ ; a group (CH₂)_(p) R₃₅ ; a (C₂-C₁₀)alkylene group substituted by R₂₁ ; a group CH₂ CN; a groupC(CH₃)(CH₂ OH)₂ or C(CH₂ OH)₃ ; a non-aromatic C₃ -C₁₈ carbocyclicradical; a phenyl group which is unsubstituted or monosubstituted orpolysubstituted by a halogen, a (C₁ -C₇)alkyl group, a hydroxyl group, a(C₁ -C₇)alkoxy group, a benzyloxy group, an acetoxy group, a nitro groupor an amino group which is free or substituted by one or two (C₁-C₇)alkyl groups; a benzyl group in which the phenyl group isunsubstituted or monosubstituted or polysubstituted by a halogen atom, a(C₁ -C₇)alkyl group, a hydroxyl group, a (C₁ -C₇)alkoxy group, abenzyloxy group, an acetoxy group, a nitro group or an amino group whichis free or substituted by one or two (C₁ -C₇)alkyl groups; a phenethylgroup in which the phenyl group is unsubstituted or monosubstituted orpolysubstituted by a halogen atom, a (C₁ -C₇)alkyl group, a hydroxylgroup, a (C₁ -C₇)alkoxy group, a benzyloxy group, an acetoxy group, anitro group or an amino group which is free or substituted by one or two(C₁ -C₇)alkyl groups; or a phenethyl group in which the phenyl group issubstituted by a 3,4-methylenedioxy group or a 3,4-ethylenedioxy group;R₁₂ is a morpholin-4-yl group; a thiomorpholin-4-yl group; anazetidin-1-yl group which is unsubstituted or substituted in the2-position by a carboxyl group or substituted in the 3-position by anamino group which is free or carries a protective group; aperhydroazepin-1-yl group; a piperazin-1-yl group which is unsubstitutedor substituted in the 4-position by R₂₅ ; a piperid-1-yl group which isunsubstituted or substituted by R₂₆ ; a pyrolidin-1-yl group which isunsubstituted or substituted by R₂₇ ; or a thiazolidin-3-yl group whichis unsubstituted or substituted by R₂₇ ; R₁₃ is a hydrogen atom; a (C₁-C₇)alkyl group; a benzyl group; an allyl group; or atetrahydropyran-2-yl group; R₁₈ is a (C₁ -C₇)alkyl group; a phenylgroup; a benzyl group; a cyclohexylmethyl group; a phenethyl group; animidizol-4-ylmethyl group which is free or carries a protective group;an indol-3-ylmethyl group which is free or carries a protective group; ahydroxymethyl group which is free or carries a protective group; a2-hydroxyethyl group which is free or carries a protective group; a1-hydroxyethyl group which is free or carries a protective group; a4-hydroxybenzyl group which is free or carries a protective group; amercaptomethyl group which is free or carries a protective group; a2-mercaptoethyl which is free or carries a protective group; a2-methylthioethyl group; a 2-methylsulfinylethyl group; a2-methylsulfonylethyl group; a 4-aminobutyl group which is free orcarries a protective group; a 3-aminopropyl group which is free orcarries a protective group; a carboxymethyl group which is free orcarries a protective group; a 2-carboxyethyl group which is free orcarries protective group; a carbamoylmethyl group; a 2-carbamoylethylgroup; a 3guanidinopropyl group which is free or carries a protectivegroup; or a non-aromatic C₃ -C₁₅, carbocyclic radical; R₁₉ is a hydrogenatom; R₁₉ can also be a (C₁ -C₇)alkyl group if R₁₈ is a (C₁ -C₇)alkylgroup; or R₁₈ and R₁₉, together with the carbon atom to which they arebonded, form a non-aromatic C₃ -C₁₅, carbocyclic radical; R₂₀ is R₂₄ ; agroup CH₂ OR₁₃ ; or an aminomethyl group in which the amino group isfree or substituted by one or two (C₁ -C₇)alkyl groups or by aprotective group; R₂₁ is R₃₆ ; a group OR₃₇ ; a cyano group; a groupS(C₁ -C₇) alkyl a group SO(C₁ -C₇)alkyl; or a group SO₂ (C₁ -C₇)alkyl;R₂₅ is a (C₁ -C₇)alkyl group; a phenyl group; a benzyl group; a formylgroup; a (C₁ -C₇)alkylcarbonyl group; a (C₁ -C₇)alkoxycarbonyl group; ora benzyloxycarbonyl group; R₂₆ is R₂₄ ; an amino group which is free orsubstituted by one or two (C₁ -C₇)alkyl groups or by a protective group;a group OR₁₃ or a group CH₂ OR₁₃ ; R₂₇ is R₂₄ ; a group CH₂ R₂₄ ; agroup CH₂ OR₁₃ ; or an aminomethyl group in which the amino group isfree or substituted by one or two (C₁ -C₇)alkyl groups or by aprotective group; R₃₅ is a piperid-4-yl group which is unsubstituted orsubstituted in the 1-position by a (C₁ -C₇)alkoxycarbonyl group or by a(C₁ -C₇)alkyl group; or a pyrid-2-yl group; R₃₂ and R₃₃ eachindependently represent a hydrogen atom; or a (C₁ -C₇)alkyl group; R₃₃can also be an acetyl group; a phenyl group; a benzyl group; a (C₁-C₇)alkoxycarbonyl group; a benzyloxycarbonyl group; a (C₁ -C₆)alkylenegroup substituted by R₂₄ ; a (C₂ -C₆)alkylene group substituted by ahydroxyl or a (C₁ -C₇)alkoxy group; or a (C₂ -C₆)alkylene groupsubstituted by an amino group which is free or substituted by one or two(C₁ -C₇)alkyl groups or by a protective group; or R₃₂ and R₃₃, togetherwith the nitrogen atom to which they are bonded, form a heterocyclicradical R₁₂ ; R₂₄ is a carboxyl group: a (C₁ -C₇)alkoxycarbonyl; abenzyloxycarbonyl group: or a carbamoyl group which is free orsubstituted by one or two (C₁ -C₇)alkyl groups: R₃₆ is a carboxyl group;a (C₁ -C₇)alkoxycarbonyl group; a benzyloxycarbonyl group; or acarbamoyl group which is free or substituted by R₃₈ and R₃₉ ; where R₃₈and R₃₉ each independently represent a hydrogen atom; or a (C₁ -C₇)alkylgroup; R₃₉ can also be a (C₁ -C₆)alkylene group substituted by R₂₄ ; a(C₂ -C₆)alkylene group substituted by a hydroxyl group or a (C₁-C₇)alkoxy group; or a (C₂ -C₆)alkylene group substituted by an aminogroup which is free or substituted by one or two (C₁ -C₇)alkyl groups orby a protective group; and R₃₇ is R₁₃ ; a (C₃ -C₇)cycloalkyl; a (C₁-C₆)alkylene substituted by R₂₄ ; a (C₂ -C₆)alkylene substituted by ahydroxyl or a (C₁ -C₇)alkoxy; or a (C₂ -C₆)alkylene substituted by anamino which is free or substituted by one or two (C₁ -C₇)alkyls or by aprotective group, and p is an integer which can vary from 0 to
 3. 2. Acompound of formula II' of claim 1, in whichR_(I) is an ethoxy group ora chlorine atom; R_(II) is hydrogen, a chlorine atom or a methyl group;R_(III) is a chlorophenyl group or a methoxyphenyl group; R_(IV) is anamino group, a group NR₉ R₁₀ or NR₉ R_(XI), or a piperazin-1-yl radicalsubstituted in the 4-position by a (C₂ -C₁₀)alkylene group substitutedby an amino group which is free or carries a protective group; R₁₀ is(CH₂)_(p) R₃₅ or a (C₂ -C₁₀)alkylene group substituted by R₂₁ ; R_(XI)is a group ω-R₃₂ R₃₃ N(C₁ -C₄)-alkylcarbonyl; and R₉, R₂₁,R₂₄, R₃₂ R₃₃,R₃₅,R₃₇, and p are as defined in claim
 1. 3. A compound of formula (II')of claim 1, in which:R_(I) and R_(II), are each independently ahydrogen, a halogen, a (C₁ -C₇) alkyl, a (C₁ -C₇) alkoxy, atrifluoromethyl, a nitro, an amino, a hydroxyl or a benzyloxy; R_(III)is a phenyl monosubstituted or polysubstituted by a halogen, a (C₁ -C₇)alkyl, a hydroxyl, a (C₁ -C₇) alkoxy, a benzyloxy or an acetoxy; R_(IV)is an azido, an amino, a 2,2-dimethylhydrazino, a group NR₇ R₈, aheterocyclic radical R₁₂ or a piperazin-1-yl radical substituted in the4-position by a (C₂ -C₁₀) alkylene group substituted by an amino groupwhich is free or carries a protective group; R₇, R₈ and R₁₂ are asdefined in claim 1, provided that R_(I) and R_(II) are notsimultaneously hydrogen.